|
Displacement of [3H]- flunitrazepam from rat GABA-A benzodiazepine receptor
|
Rattus norvegicus
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Antagonist, partial agonist, and full agonist imidazo[1,5-a]quinoxaline amides and carbamates acting through the GABAA/benzodiazepine receptor.
Year : 1994
Volume : 37
Issue : 6
First Page : 758
Last Page : 768
Authors : TenBrink RE, Im WB, Sethy VH, Tang AH, Carter DB.
Abstract : (4RS)-1-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihyd roimidazo[1,5- a]pyrrolo[2,1-c]quinoxalin-10(11H)-one (1a), 5-benzoyl-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5- dihydroimidazo[1,5-a]quinoxaline (13b), and tert-butyl (4S)-12,12a-dihydroimidazo[1,5-a]pyrrolo[2,1- c]quinoxaline-1-carboxylate (1e), as well as other imidazo[1,5-a]quinoxaline amides and carbamates, represent a new series of compounds which bind with high affinity to the GABAA/benzodiazepine receptor. These compounds exhibit a wide range of intrinsic efficacies as measured by [35S]TBPS binding ratios. The synthesis of 1a begins with the addition of DL-glutamic acid to 1-fluoro-2-nitrobenzene, followed by reduction of the nitro group and subsequent ring closure to form 3-(carbethoxymethyl)-1,2,3,4-tetrahydroquinoxalin-2-one, followed by a second ring closure to afford (4RS)-1,5-dioxo-1,2,3,4,5,6-hexahydropyrrolo[1,2-a]quinoxali ne as the key intermediate. Appendage of a substituted imidazo ring via the anion of 5-cyclopropyl-1,2,4-oxadiazol-3-yl gives 1a. The (-)- and (+)-isomers of 1a were prepared from 1-fluoro-2-nitrobenzene and L- and D-glutamic acid, respectively. 1a and its enantiomers demonstrated affinity for the [3H]flunitrazepam binding site with Ki's of 0.87, 0.62, and 0.65 nM, respectively.
|
Displacement of [3H]flunitrazepam from rat brain GABA-A Benzodiazepine receptor
|
Rattus norvegicus
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and binding affinity of 2-phenylimidazo[1,2-alpha]pyridine derivatives for both central and peripheral benzodiazepine receptors. A new series of high-affinity and selective ligands for the peripheral type.
Year : 1997
Volume : 40
Issue : 19
First Page : 3109
Last Page : 3118
Authors : Trapani G, Franco M, Ricciardi L, Latrofa A, Genchi G, Sanna E, Tuveri F, Cagetti E, Biggio G, Liso G.
Abstract : A number of 6-substituted or 6,8-disubstituted alkyl 2-phenylimidazo[1,2-alpha]pyridine-3-carboxylates 5a-h, -acetates 5i-s, 6a-g, and -propionates 5t, 6h and of N,N-dialkyl-2-phenylimidazo[1,2-alpha]pyridine-3-carboxamides 7a-d,-acetamides 7e-t or -propionamide 7u were prepared following new synthetic methods, and their affinities for both the central (CBR) and the peripheral (PBR) benzodiazepine receptors evaluated. The compounds of the ester series displayed low affinity for both receptor types. Conversely, most of N,N-dialkyl(2-phenylimidazo[1,2-alpha]pyridin-3-yl)acetamides 7e-t proved to possess high affinity and selectivity for CBR or PBR depending on the nature of substituents at C(6)- and/or C(8) on the heterocyclic ring system. In particular, the 6-substituted compounds 7f-n displayed ratios of IC50 values (IC50(CBR)/IC50(PBR)) ranging from 0.32 (7m) to 232 (7k), while the 6,8-disubstituted compounds 7o-t were more than 1000-fold more selective for PBR versus CBR. Compounds 7f,m were examined in several different benzodiazepine receptor subtypes. Expression of specific GABAA, receptor subunit assemblies in Xenopus oocytes was utilized to evaluate functionally both the efficacy and potency of the positive modulation of GABA-evoked Cl- currents by 7f and 7m in comparison with Zolpidem. The rank order of potencies of these drugs was 7f (EC50 = 3.2 x 10(-8) M) > Zolpidem (EC50 = 3.6 x 10(-8) M) > 7m (EC50 = 2.2 x 10(-7) M). The actions of these compounds were also tested on alpha 2 beta 2 gamma 2s, receptors. However, the EC50 of these compounds was increased, compared to alpha 1 beta 2 gamma 2s receptors, by 30-, 4-, and 5-fold for 7m, 7f, and Zolpidem, respectively. Finally, these compounds were almost completely devoid of activity at receptors containing the alpha 5 subunit.
|
Effective concentration against gamma-aminobutyric acid (GABA) A receptor, alpha 2
|
Xenopus laevis
|
737.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABA(A) receptor.
Year : 2002
Volume : 45
Issue : 23
First Page : 5043
Last Page : 5051
Authors : Albaugh PA, Marshall L, Gregory J, White G, Hutchison A, Ross PC, Gallagher DW, Tallman JF, Crago M, Cassella JV.
Abstract : Benzodiazepines are allosteric modulators of the GABA(A) receptor. The traditionally prescribed benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification of receptor subtypes, we set out to discover selective agents with the anticipation that these agents would have superior therapeutic potential. Herein, we describe the synthesis and biological evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-ones and disclose that these compounds exhibit functional selectivity at the benzodiazepine receptor of GABA(A) receptor subtypes. The alpha(2)/alpha(3)-selective partial agonist 42 exhibited potent in vivo activity.
|
Displacement of [3H]-Ro-15-1788 from rat GABA-A receptor alpha-2-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
156.0
nM
|
|
Journal : J. Med. Chem.
Title : Benzodiazepine receptor ligands. 7. Synthesis and pharmacological evaluation of new 3-esters of the 8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide. 3-(2-Thienylmethoxycarbonyl) derivative: an anxioselective agent in rodents.
Year : 2002
Volume : 45
Issue : 26
First Page : 5710
Last Page : 5720
Authors : Costanzo A, Guerrini G, Ciciani G, Bruni F, Costagli C, Selleri S, Besnard F, Costa B, Martini C, Malmberg-Aiello P.
Abstract : The synthesis and binding study of new 8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide 3-ester compounds are reported. A pharmacological evaluation of the high-affinity ligands 1-4 belonging to the 3-heteroarylester series is made. The 3-(2-thienylmethoxycarbonyl) derivative 4 stands out from the other heteroarylesters and is found, using nine different behavioral methods, to be a functionally selective ligand in vivo: it shows anxiolytic-like activity in the conflict models (light-dark box and plus maze test) similarly to diazepam, without any sedative and amnesic properties or interference from alcohol.
|
Displacement of [3H]Ro-151788 from rat GABA-A receptor alpha-3-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
383.0
nM
|
|
Journal : J. Med. Chem.
Title : Benzodiazepine receptor ligands. 7. Synthesis and pharmacological evaluation of new 3-esters of the 8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide. 3-(2-Thienylmethoxycarbonyl) derivative: an anxioselective agent in rodents.
Year : 2002
Volume : 45
Issue : 26
First Page : 5710
Last Page : 5720
Authors : Costanzo A, Guerrini G, Ciciani G, Bruni F, Costagli C, Selleri S, Besnard F, Costa B, Martini C, Malmberg-Aiello P.
Abstract : The synthesis and binding study of new 8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide 3-ester compounds are reported. A pharmacological evaluation of the high-affinity ligands 1-4 belonging to the 3-heteroarylester series is made. The 3-(2-thienylmethoxycarbonyl) derivative 4 stands out from the other heteroarylesters and is found, using nine different behavioral methods, to be a functionally selective ligand in vivo: it shows anxiolytic-like activity in the conflict models (light-dark box and plus maze test) similarly to diazepam, without any sedative and amnesic properties or interference from alcohol.
|
Binding affinity to rat chimeric GABA-A receptor C6, alpha1-alpha6 chimeric subunit co-expressed with beta-2 gamma2 subunits in HEK293 cells
|
Rattus norvegicus
|
125.0
nM
|
|
Journal : J. Med. Chem.
Title : Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor.
Year : 1994
Volume : 37
Issue : 26
First Page : 4576
Last Page : 4580
Authors : Wieland HA, Lüddens H.
Abstract : Benzodiazepines (BZ) exert their effects through GABAA receptors, which belong to the superfamily of ligand-gated ion channels. Coexpression of recombinant alpha, beta, and gamma subunits in a cell culture system mimics the BZ binding sites. The alpha variants largely determine the nature of the BZ binding site in such alpha i beta j gamma k heteromultimers (i = 1-6; j = 1-3; k = 1-3). Notably, the alpha 1 and alpha 6 variants confer high and low affinity for BZ agonists to the resulting receptor subtype, respectively. Glycine/glutamate and histidine/arginine positions in the alpha subunits of alpha x beta 2 gamma 2 receptors are involved in BZ I versus BZ II type selectivity. We now identify four amino acids in alpha 6 which together increase the affinity of the mutant alpha x beta 2 gamma 2 receptor for classical BZ receptor agonists above the level seen for any wild-type GABAA/BZ receptor. The most pronounced effect was due to an isoleucine to valine exchange. It simultaneously decreased the affinity for the BZ partial inverse agonist Ro 15-4513 20-fold and increased the affinity for diazepam 4-fold. The four amino acid residues stretch over most part of the N-terminal extracellular domain of the alpha subunit, suggesting that amino acids distant in the primary sequence form the BZ binding pocket.
|
Inhibition of [3H]flumazenil specific binding at rat GABA-A alpha-1-beta-2-gamma-2 receptor subunits expressed in HEK293 cells
|
Rattus norvegicus
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel N-(arylalkyl)indol-3-ylglyoxylylamides targeted as ligands of the benzodiazepine receptor: synthesis, biological evaluation, and molecular modeling analysis of the structure-activity relationships.
Year : 2001
Volume : 44
Issue : 14
First Page : 2286
Last Page : 2297
Authors : Primofiore G, Settimo FD, Taliani S, Marini AM, Novellino E, Greco G, Lavecchia A, Besnard F, Trincavelli L, Costa B, Martini C.
Abstract : A series of N-(arylalkyl)indol-3-ylglyoxylylamides (4-8) was synthesized as ligands of the benzodiazepine receptor (BzR) and tested for their ability to displace [(3)H]flumazenil from bovine brain membranes. The new compounds, bearing a branched (4) or a geometrically constrained benzyl/phenylethyl amide side chain (5-8), represent the continuation of our research on N-benzylindol-3-ylglyoxylylamides 1 (Da Settimo et al., 1996), N'-phenylindol-3-ylglyoxylohydrazides 2 (Da Settimo et al., 1998), and N-(indol-3-ylglyoxylyl)alanine derivatives 3 (Primofiore et al., 1989). A few indoles belonging to the previously investigated benzylamides 1 and phenylhydrazides 2 were synthesized and tested to enrich the SARs in these two series. The affinities and the GABA ratios of selected compounds for clonal mammalian alpha(1)beta(2)gamma(2), alpha(3)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzR subtypes were also determined. It was hypothesized that the reduced flexibility of indoles 4-8 would both facilitate the mapping of the BzR binding cleft and increase the chances of conferring selectivity for the considered receptor subtypes. In the series of indoles 4, the introduction of a methyl group on the benzylic carbon with the R configuration improved affinity of the 5-substituted (5-Cl and 5-NO(2)) derivatives, whereas it was detrimental for their 5-unsubtituted (5-H) counterparts. All S enantiomers were less potent than the R ones. Replacement of the methyl with hydrophilic substituents on the benzylic carbon lowered affinity. The isoindolinylamide side chain was tolerated if the 5-position was unsubstituted (K(i) of 5a = 123 nM), otherwise affinity was abolished (5b, c). All the 2-indanylamides 6 and (S)-1-indanylamides 8 were devoid of any appreciable affinity. The 5-Cl and 5-NO(2) (R)-1-indanylamides 7b (K(i) 80 nM) and 7c (K(i) 28 nM) were the most potent among the indoles 5-8 geometrically constrained about the side chain. The 5-H (R)-1-indanylamide 7a displayed a lower affinity (K(i) 675 nM). The SARs developed from the new compounds, together with those collected from our previous studies, confirmed the hypothesis of different binding modes for 5-substituted and 5-unsubstituted indoles, suggesting that the shape of the lipophilic pocket L(1) (notation in accordance with Cook's BzR topological model) is asymmetric and highlighted the stereoelectronic and conformational properties of the amide side chain required for high potency. Several of the new indoles showed selectivity for the alpha(1)beta(2)gamma(2) subtype compared with the alpha(3)beta(2)gamma(2) and alpha(5)beta(3)gamma(2) subtypes (e.g.: 4t and 7c bind to these three BzR isoforms with K(i) values of 14 nM, 283 nM, 239 nM, and 9 nM, 1960 nM, 95 nM, respectively). The GABA ratios close to unity exhibited by all the tested compounds on each BzR subtype were predictive of an efficacy profile typical of antagonists.
|
Binding affinity for human GABA-A receptor alpha-4-beta-3-gamma-2 subunits in L(tk-) cells
|
Homo sapiens
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and analogues: high-affinity gamma-aminobutyric acid-A benzodiazepine receptor ligands with alpha 2, alpha 3, and alpha 5-subtype binding selectivity over alpha 1.
Year : 2004
Volume : 47
Issue : 7
First Page : 1807
Last Page : 1822
Authors : Carling RW, Moore KW, Street LJ, Wild D, Isted C, Leeson PD, Thomas S, O'Connor D, McKernan RM, Quirk K, Cook SM, Atack JR, Wafford KA, Thompson SA, Dawson GR, Ferris P, Castro JL.
Abstract : Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha 3- and alpha 5-containing receptor subtypes over the GABA-A alpha 1 subtype (K(i): alpha 2 = 850 nM, alpha 3 = 170 nM, alpha 5 = 72 nM, alpha 1 = 1400 nM). Early optimization studies identified the close analogue 10 (K(i): alpha 2 = 16 nM, alpha 3 = 41 nM, alpha 5 = 38 nM, alpha 1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K(i): alpha 2 = 1.7 nM, alpha 3 = 0.71 nM, alpha 5 = 0.33 nM, alpha 1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha 1, -7%; alpha 2, -5%; alpha 3, -16%; alpha 5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha 3 over alpha 1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha 3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of 1 h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha 2/alpha 3 agonist in vivo.
|
Inhibition of [3H]flumazenil binding to recombinant GABA-A receptor alpha-1 subunit in cerebellum
|
None
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A conformational study of ligands for omega modulatory sites of GABAa receptors by NOESY NMR spectroscopy and distance geometry
Year : 1997
Volume : 7
Issue : 17
First Page : 2277
Last Page : 2282
Authors : Olivier A, Sevrin M, Durant F, George P
|
Inhibition of [3H]flumazenil binding to recombinant GABA-A receptor alpha-1 subunit in spinal cord
|
None
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A conformational study of ligands for omega modulatory sites of GABAa receptors by NOESY NMR spectroscopy and distance geometry
Year : 1997
Volume : 7
Issue : 17
First Page : 2277
Last Page : 2282
Authors : Olivier A, Sevrin M, Durant F, George P
|
Binding affinity for human GABA-A receptor alpha-2-beta-3-gamma-2 subunits in L(tk-) cells
|
Homo sapiens
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and analogues: high-affinity gamma-aminobutyric acid-A benzodiazepine receptor ligands with alpha 2, alpha 3, and alpha 5-subtype binding selectivity over alpha 1.
Year : 2004
Volume : 47
Issue : 7
First Page : 1807
Last Page : 1822
Authors : Carling RW, Moore KW, Street LJ, Wild D, Isted C, Leeson PD, Thomas S, O'Connor D, McKernan RM, Quirk K, Cook SM, Atack JR, Wafford KA, Thompson SA, Dawson GR, Ferris P, Castro JL.
Abstract : Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha 3- and alpha 5-containing receptor subtypes over the GABA-A alpha 1 subtype (K(i): alpha 2 = 850 nM, alpha 3 = 170 nM, alpha 5 = 72 nM, alpha 1 = 1400 nM). Early optimization studies identified the close analogue 10 (K(i): alpha 2 = 16 nM, alpha 3 = 41 nM, alpha 5 = 38 nM, alpha 1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K(i): alpha 2 = 1.7 nM, alpha 3 = 0.71 nM, alpha 5 = 0.33 nM, alpha 1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha 1, -7%; alpha 2, -5%; alpha 3, -16%; alpha 5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha 3 over alpha 1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha 3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of 1 h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha 2/alpha 3 agonist in vivo.
|
Binding affinity for human GABA-A receptor alpha-3-beta-3-gamma-2 subunits in L(tk-) cells
|
Homo sapiens
|
380.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and analogues: high-affinity gamma-aminobutyric acid-A benzodiazepine receptor ligands with alpha 2, alpha 3, and alpha 5-subtype binding selectivity over alpha 1.
Year : 2004
Volume : 47
Issue : 7
First Page : 1807
Last Page : 1822
Authors : Carling RW, Moore KW, Street LJ, Wild D, Isted C, Leeson PD, Thomas S, O'Connor D, McKernan RM, Quirk K, Cook SM, Atack JR, Wafford KA, Thompson SA, Dawson GR, Ferris P, Castro JL.
Abstract : Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha 3- and alpha 5-containing receptor subtypes over the GABA-A alpha 1 subtype (K(i): alpha 2 = 850 nM, alpha 3 = 170 nM, alpha 5 = 72 nM, alpha 1 = 1400 nM). Early optimization studies identified the close analogue 10 (K(i): alpha 2 = 16 nM, alpha 3 = 41 nM, alpha 5 = 38 nM, alpha 1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K(i): alpha 2 = 1.7 nM, alpha 3 = 0.71 nM, alpha 5 = 0.33 nM, alpha 1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha 1, -7%; alpha 2, -5%; alpha 3, -16%; alpha 5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha 3 over alpha 1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha 3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of 1 h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha 2/alpha 3 agonist in vivo.
|
Displacement of [3H]Ro-151788 from rat GABA-A receptor alpha-1-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
26.7
nM
|
|
Journal : J. Med. Chem.
Title : Benzodiazepine receptor ligands. 7. Synthesis and pharmacological evaluation of new 3-esters of the 8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide. 3-(2-Thienylmethoxycarbonyl) derivative: an anxioselective agent in rodents.
Year : 2002
Volume : 45
Issue : 26
First Page : 5710
Last Page : 5720
Authors : Costanzo A, Guerrini G, Ciciani G, Bruni F, Costagli C, Selleri S, Besnard F, Costa B, Martini C, Malmberg-Aiello P.
Abstract : The synthesis and binding study of new 8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide 3-ester compounds are reported. A pharmacological evaluation of the high-affinity ligands 1-4 belonging to the 3-heteroarylester series is made. The 3-(2-thienylmethoxycarbonyl) derivative 4 stands out from the other heteroarylesters and is found, using nine different behavioral methods, to be a functionally selective ligand in vivo: it shows anxiolytic-like activity in the conflict models (light-dark box and plus maze test) similarly to diazepam, without any sedative and amnesic properties or interference from alcohol.
|
Binding affinity for recombinant rat GABA-A receptor alpha-1-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
26.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and benzodiazepine receptor affinity of pyrazolo[1,5-a]pyrimidine derivatives. 3. New 6-(3-thienyl) series as alpha 1 selective ligands.
Year : 2003
Volume : 46
Issue : 2
First Page : 310
Last Page : 313
Authors : Selleri S, Bruni F, Costagli C, Costanzo A, Guerrini G, Ciciani G, Gratteri P, Bonaccini C, Malmberg Aiello P, Besnard F, Renard S, Costa B, Martini C.
Abstract : New 3-aryl-6-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-ones (2a-j) are synthesized and evaluated in vitro on Bz/GABA(A) receptors and on recombinant benzodiazepine receptors (alpha x beta 2/3 gamma 2; x = 1-3, 5) expressed in HEK293 cells. SAR studies on the new compounds are conducted and molecular modeling is accomplished to better investigate requirements leading to subtype selectivity. Some of the synthesized compounds are tested in vivo to explore their pharmacological effect as a consequence of their high alpha 1 beta 2 gamma 2 subtype selectivity observed in vitro.
|
Inhibition of [3H]flumazenil binding to recombinant GABA-A receptor alpha-1-beta-2-gamma-2 subunits
|
None
|
46.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A conformational study of ligands for omega modulatory sites of GABAa receptors by NOESY NMR spectroscopy and distance geometry
Year : 1997
Volume : 7
Issue : 17
First Page : 2277
Last Page : 2282
Authors : Olivier A, Sevrin M, Durant F, George P
|
Binding affinity towards human alpha-1-beta-3-gamma-2 GABA-A receptor using [3H]Ro-151788 expressed in L(tk-) cells
|
None
|
52.1
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABA(A)alpha5 benzodiazepine binding site.
Year : 2004
Volume : 47
Issue : 14
First Page : 3642
Last Page : 3657
Authors : Street LJ, Sternfeld F, Jelley RA, Reeve AJ, Carling RW, Moore KW, McKernan RM, Sohal B, Cook S, Pike A, Dawson GR, Bromidge FA, Wafford KA, Seabrook GR, Thompson SA, Marshall G, Pillai GV, Castro JL, Atack JR, MacLeod AM.
Abstract : The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.
|
Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-1-beta-3-gamma-2
|
None
|
26.7
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore/receptor models for GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) via a comprehensive ligand-mapping approach.
Year : 2000
Volume : 43
Issue : 1
First Page : 71
Last Page : 95
Authors : Huang Q, He X, Ma C, Liu R, Yu S, Dayer CA, Wenger GR, McKernan R, Cook JM.
Abstract : Pharmacophore/receptor models for three recombinant GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) have been established via an SAR ligand-mapping approach. This study was based on the affinities of 151 BzR ligands at five distinct (alpha1-3,5,6beta3gamma2) recombinant GABA(A)/BzR receptor subtypes from at least nine different structural families. Examination of the included volumes of the alpha1-, alpha5-, and alpha6-containing subtypes indicated that region L(2) for the alpha5-containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region L(Di), in contrast, appeared to be larger in the alpha1 subtype than in the other two subtypes. Moreover, region L(3) in the alpha6 subtype is either very small or nonexistent in this diazepam-insensitive subtype (see Figure 16 for details) as compared to the other subtypes. Use of the pharmacophore/receptor models for these subtypes has resulted in the design of novel BzR ligands (see 27) selective for the alpha5beta3gamma2 receptor subtype. alpha5-Selective ligand 27 when injected directly into the hippocampus did enhance memory in one paradigm (Bailey et al., unpublished observations); however, systemic administration of either 9 or 27 into animals did not provide an observable enhancement. This result is in complete agreement with the observation of Liu (1996). It has been shown (Liu, 1996; Wisden et al., 1992) that in the central nervous system of the rat (as well as monkeys and pigeons) there are several native subtypes of the GABA(A) receptor which exhibit different functions, regional distributions, and neuronal locations. Although 27 binds more potently at alpha5beta3gamma2 receptor subtypes and is clearly an inverse agonist (Liu et al., 1996; Liu, 1996), it is possible that this ligand acts as an agonist at one or more subtypes. Liu (1996) clearly showed that a number of imidazobenzodiazepines were negative modulators at one subtype and agonists at another. Therefore, selectivity for a particular subtype at this point is not sufficient to rule out some physiological effect at other GABA(A)/BzR subtypes. The inability of 27 to potentiate memory when given systemically is again in support of this hypothesis, especially since alpha1beta2gamma2 subtypes are distributed throughout the brain (Wisden et al., 1992). A drug delivered systemically is far more likely to interact with all subtypes than one delivered to a specific brain region. This observation (systemic vs intrahippocampal) provides further support for the design of more subtype-specific ligands at the BzR to accurately define their pharmacology, one key to the design of new drugs with fewer side effects.
|
Binding affinity for recombinant rat GABA-A receptor alpha-2-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
156.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and benzodiazepine receptor affinity of pyrazolo[1,5-a]pyrimidine derivatives. 3. New 6-(3-thienyl) series as alpha 1 selective ligands.
Year : 2003
Volume : 46
Issue : 2
First Page : 310
Last Page : 313
Authors : Selleri S, Bruni F, Costagli C, Costanzo A, Guerrini G, Ciciani G, Gratteri P, Bonaccini C, Malmberg Aiello P, Besnard F, Renard S, Costa B, Martini C.
Abstract : New 3-aryl-6-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-ones (2a-j) are synthesized and evaluated in vitro on Bz/GABA(A) receptors and on recombinant benzodiazepine receptors (alpha x beta 2/3 gamma 2; x = 1-3, 5) expressed in HEK293 cells. SAR studies on the new compounds are conducted and molecular modeling is accomplished to better investigate requirements leading to subtype selectivity. Some of the synthesized compounds are tested in vivo to explore their pharmacological effect as a consequence of their high alpha 1 beta 2 gamma 2 subtype selectivity observed in vitro.
|
Binding affinity towards human gamma-aminobutyric-acid A receptor alpha-2-beta-3-gamma-2 using [3H]Ro-151788 expressed in L(tk-) cells
|
None
|
255.1
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABA(A)alpha5 benzodiazepine binding site.
Year : 2004
Volume : 47
Issue : 14
First Page : 3642
Last Page : 3657
Authors : Street LJ, Sternfeld F, Jelley RA, Reeve AJ, Carling RW, Moore KW, McKernan RM, Sohal B, Cook S, Pike A, Dawson GR, Bromidge FA, Wafford KA, Seabrook GR, Thompson SA, Marshall G, Pillai GV, Castro JL, Atack JR, MacLeod AM.
Abstract : The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.
|
Binding affinity to human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-2-beta-3-gamma-2
|
None
|
156.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore/receptor models for GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) via a comprehensive ligand-mapping approach.
Year : 2000
Volume : 43
Issue : 1
First Page : 71
Last Page : 95
Authors : Huang Q, He X, Ma C, Liu R, Yu S, Dayer CA, Wenger GR, McKernan R, Cook JM.
Abstract : Pharmacophore/receptor models for three recombinant GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) have been established via an SAR ligand-mapping approach. This study was based on the affinities of 151 BzR ligands at five distinct (alpha1-3,5,6beta3gamma2) recombinant GABA(A)/BzR receptor subtypes from at least nine different structural families. Examination of the included volumes of the alpha1-, alpha5-, and alpha6-containing subtypes indicated that region L(2) for the alpha5-containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region L(Di), in contrast, appeared to be larger in the alpha1 subtype than in the other two subtypes. Moreover, region L(3) in the alpha6 subtype is either very small or nonexistent in this diazepam-insensitive subtype (see Figure 16 for details) as compared to the other subtypes. Use of the pharmacophore/receptor models for these subtypes has resulted in the design of novel BzR ligands (see 27) selective for the alpha5beta3gamma2 receptor subtype. alpha5-Selective ligand 27 when injected directly into the hippocampus did enhance memory in one paradigm (Bailey et al., unpublished observations); however, systemic administration of either 9 or 27 into animals did not provide an observable enhancement. This result is in complete agreement with the observation of Liu (1996). It has been shown (Liu, 1996; Wisden et al., 1992) that in the central nervous system of the rat (as well as monkeys and pigeons) there are several native subtypes of the GABA(A) receptor which exhibit different functions, regional distributions, and neuronal locations. Although 27 binds more potently at alpha5beta3gamma2 receptor subtypes and is clearly an inverse agonist (Liu et al., 1996; Liu, 1996), it is possible that this ligand acts as an agonist at one or more subtypes. Liu (1996) clearly showed that a number of imidazobenzodiazepines were negative modulators at one subtype and agonists at another. Therefore, selectivity for a particular subtype at this point is not sufficient to rule out some physiological effect at other GABA(A)/BzR subtypes. The inability of 27 to potentiate memory when given systemically is again in support of this hypothesis, especially since alpha1beta2gamma2 subtypes are distributed throughout the brain (Wisden et al., 1992). A drug delivered systemically is far more likely to interact with all subtypes than one delivered to a specific brain region. This observation (systemic vs intrahippocampal) provides further support for the design of more subtype-specific ligands at the BzR to accurately define their pharmacology, one key to the design of new drugs with fewer side effects.
|
Binding affinity for recombinant rat GABA-A receptor alpha-3-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
383.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and benzodiazepine receptor affinity of pyrazolo[1,5-a]pyrimidine derivatives. 3. New 6-(3-thienyl) series as alpha 1 selective ligands.
Year : 2003
Volume : 46
Issue : 2
First Page : 310
Last Page : 313
Authors : Selleri S, Bruni F, Costagli C, Costanzo A, Guerrini G, Ciciani G, Gratteri P, Bonaccini C, Malmberg Aiello P, Besnard F, Renard S, Costa B, Martini C.
Abstract : New 3-aryl-6-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-ones (2a-j) are synthesized and evaluated in vitro on Bz/GABA(A) receptors and on recombinant benzodiazepine receptors (alpha x beta 2/3 gamma 2; x = 1-3, 5) expressed in HEK293 cells. SAR studies on the new compounds are conducted and molecular modeling is accomplished to better investigate requirements leading to subtype selectivity. Some of the synthesized compounds are tested in vivo to explore their pharmacological effect as a consequence of their high alpha 1 beta 2 gamma 2 subtype selectivity observed in vitro.
|
Inhibition of [3H]-flumazenil binding to rat GABA-A receptor alpha-3-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
765.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel N-(arylalkyl)indol-3-ylglyoxylylamides targeted as ligands of the benzodiazepine receptor: synthesis, biological evaluation, and molecular modeling analysis of the structure-activity relationships.
Year : 2001
Volume : 44
Issue : 14
First Page : 2286
Last Page : 2297
Authors : Primofiore G, Settimo FD, Taliani S, Marini AM, Novellino E, Greco G, Lavecchia A, Besnard F, Trincavelli L, Costa B, Martini C.
Abstract : A series of N-(arylalkyl)indol-3-ylglyoxylylamides (4-8) was synthesized as ligands of the benzodiazepine receptor (BzR) and tested for their ability to displace [(3)H]flumazenil from bovine brain membranes. The new compounds, bearing a branched (4) or a geometrically constrained benzyl/phenylethyl amide side chain (5-8), represent the continuation of our research on N-benzylindol-3-ylglyoxylylamides 1 (Da Settimo et al., 1996), N'-phenylindol-3-ylglyoxylohydrazides 2 (Da Settimo et al., 1998), and N-(indol-3-ylglyoxylyl)alanine derivatives 3 (Primofiore et al., 1989). A few indoles belonging to the previously investigated benzylamides 1 and phenylhydrazides 2 were synthesized and tested to enrich the SARs in these two series. The affinities and the GABA ratios of selected compounds for clonal mammalian alpha(1)beta(2)gamma(2), alpha(3)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzR subtypes were also determined. It was hypothesized that the reduced flexibility of indoles 4-8 would both facilitate the mapping of the BzR binding cleft and increase the chances of conferring selectivity for the considered receptor subtypes. In the series of indoles 4, the introduction of a methyl group on the benzylic carbon with the R configuration improved affinity of the 5-substituted (5-Cl and 5-NO(2)) derivatives, whereas it was detrimental for their 5-unsubtituted (5-H) counterparts. All S enantiomers were less potent than the R ones. Replacement of the methyl with hydrophilic substituents on the benzylic carbon lowered affinity. The isoindolinylamide side chain was tolerated if the 5-position was unsubstituted (K(i) of 5a = 123 nM), otherwise affinity was abolished (5b, c). All the 2-indanylamides 6 and (S)-1-indanylamides 8 were devoid of any appreciable affinity. The 5-Cl and 5-NO(2) (R)-1-indanylamides 7b (K(i) 80 nM) and 7c (K(i) 28 nM) were the most potent among the indoles 5-8 geometrically constrained about the side chain. The 5-H (R)-1-indanylamide 7a displayed a lower affinity (K(i) 675 nM). The SARs developed from the new compounds, together with those collected from our previous studies, confirmed the hypothesis of different binding modes for 5-substituted and 5-unsubstituted indoles, suggesting that the shape of the lipophilic pocket L(1) (notation in accordance with Cook's BzR topological model) is asymmetric and highlighted the stereoelectronic and conformational properties of the amide side chain required for high potency. Several of the new indoles showed selectivity for the alpha(1)beta(2)gamma(2) subtype compared with the alpha(3)beta(2)gamma(2) and alpha(5)beta(3)gamma(2) subtypes (e.g.: 4t and 7c bind to these three BzR isoforms with K(i) values of 14 nM, 283 nM, 239 nM, and 9 nM, 1960 nM, 95 nM, respectively). The GABA ratios close to unity exhibited by all the tested compounds on each BzR subtype were predictive of an efficacy profile typical of antagonists.
|
Binding affinity towards human gamma-aminobutyric-acid A receptor alpha-3-beta-3-gamma-2 using [3H]Ro-151788 expressed in L(tk-) cells
|
None
|
608.5
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABA(A)alpha5 benzodiazepine binding site.
Year : 2004
Volume : 47
Issue : 14
First Page : 3642
Last Page : 3657
Authors : Street LJ, Sternfeld F, Jelley RA, Reeve AJ, Carling RW, Moore KW, McKernan RM, Sohal B, Cook S, Pike A, Dawson GR, Bromidge FA, Wafford KA, Seabrook GR, Thompson SA, Marshall G, Pillai GV, Castro JL, Atack JR, MacLeod AM.
Abstract : The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.
|
Binding affinity for human recombinant gamma-aminobutyric-acid (GABA) A receptor alpha-3-beta-3-gamma-2
|
None
|
383.0
nM
|
|
Journal : J. Med. Chem.
Title : Pharmacophore/receptor models for GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) via a comprehensive ligand-mapping approach.
Year : 2000
Volume : 43
Issue : 1
First Page : 71
Last Page : 95
Authors : Huang Q, He X, Ma C, Liu R, Yu S, Dayer CA, Wenger GR, McKernan R, Cook JM.
Abstract : Pharmacophore/receptor models for three recombinant GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) have been established via an SAR ligand-mapping approach. This study was based on the affinities of 151 BzR ligands at five distinct (alpha1-3,5,6beta3gamma2) recombinant GABA(A)/BzR receptor subtypes from at least nine different structural families. Examination of the included volumes of the alpha1-, alpha5-, and alpha6-containing subtypes indicated that region L(2) for the alpha5-containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region L(Di), in contrast, appeared to be larger in the alpha1 subtype than in the other two subtypes. Moreover, region L(3) in the alpha6 subtype is either very small or nonexistent in this diazepam-insensitive subtype (see Figure 16 for details) as compared to the other subtypes. Use of the pharmacophore/receptor models for these subtypes has resulted in the design of novel BzR ligands (see 27) selective for the alpha5beta3gamma2 receptor subtype. alpha5-Selective ligand 27 when injected directly into the hippocampus did enhance memory in one paradigm (Bailey et al., unpublished observations); however, systemic administration of either 9 or 27 into animals did not provide an observable enhancement. This result is in complete agreement with the observation of Liu (1996). It has been shown (Liu, 1996; Wisden et al., 1992) that in the central nervous system of the rat (as well as monkeys and pigeons) there are several native subtypes of the GABA(A) receptor which exhibit different functions, regional distributions, and neuronal locations. Although 27 binds more potently at alpha5beta3gamma2 receptor subtypes and is clearly an inverse agonist (Liu et al., 1996; Liu, 1996), it is possible that this ligand acts as an agonist at one or more subtypes. Liu (1996) clearly showed that a number of imidazobenzodiazepines were negative modulators at one subtype and agonists at another. Therefore, selectivity for a particular subtype at this point is not sufficient to rule out some physiological effect at other GABA(A)/BzR subtypes. The inability of 27 to potentiate memory when given systemically is again in support of this hypothesis, especially since alpha1beta2gamma2 subtypes are distributed throughout the brain (Wisden et al., 1992). A drug delivered systemically is far more likely to interact with all subtypes than one delivered to a specific brain region. This observation (systemic vs intrahippocampal) provides further support for the design of more subtype-specific ligands at the BzR to accurately define their pharmacology, one key to the design of new drugs with fewer side effects.
|
Inhibition of [3H]flumazenil binding to rat GABA-A receptor alpha-5-beta-3-gamma-2 subunits expressed in HEK293 cells at 10 uM
|
Rattus norvegicus
|
35.0
%
|
|
Journal : J. Med. Chem.
Title : Novel N-(arylalkyl)indol-3-ylglyoxylylamides targeted as ligands of the benzodiazepine receptor: synthesis, biological evaluation, and molecular modeling analysis of the structure-activity relationships.
Year : 2001
Volume : 44
Issue : 14
First Page : 2286
Last Page : 2297
Authors : Primofiore G, Settimo FD, Taliani S, Marini AM, Novellino E, Greco G, Lavecchia A, Besnard F, Trincavelli L, Costa B, Martini C.
Abstract : A series of N-(arylalkyl)indol-3-ylglyoxylylamides (4-8) was synthesized as ligands of the benzodiazepine receptor (BzR) and tested for their ability to displace [(3)H]flumazenil from bovine brain membranes. The new compounds, bearing a branched (4) or a geometrically constrained benzyl/phenylethyl amide side chain (5-8), represent the continuation of our research on N-benzylindol-3-ylglyoxylylamides 1 (Da Settimo et al., 1996), N'-phenylindol-3-ylglyoxylohydrazides 2 (Da Settimo et al., 1998), and N-(indol-3-ylglyoxylyl)alanine derivatives 3 (Primofiore et al., 1989). A few indoles belonging to the previously investigated benzylamides 1 and phenylhydrazides 2 were synthesized and tested to enrich the SARs in these two series. The affinities and the GABA ratios of selected compounds for clonal mammalian alpha(1)beta(2)gamma(2), alpha(3)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzR subtypes were also determined. It was hypothesized that the reduced flexibility of indoles 4-8 would both facilitate the mapping of the BzR binding cleft and increase the chances of conferring selectivity for the considered receptor subtypes. In the series of indoles 4, the introduction of a methyl group on the benzylic carbon with the R configuration improved affinity of the 5-substituted (5-Cl and 5-NO(2)) derivatives, whereas it was detrimental for their 5-unsubtituted (5-H) counterparts. All S enantiomers were less potent than the R ones. Replacement of the methyl with hydrophilic substituents on the benzylic carbon lowered affinity. The isoindolinylamide side chain was tolerated if the 5-position was unsubstituted (K(i) of 5a = 123 nM), otherwise affinity was abolished (5b, c). All the 2-indanylamides 6 and (S)-1-indanylamides 8 were devoid of any appreciable affinity. The 5-Cl and 5-NO(2) (R)-1-indanylamides 7b (K(i) 80 nM) and 7c (K(i) 28 nM) were the most potent among the indoles 5-8 geometrically constrained about the side chain. The 5-H (R)-1-indanylamide 7a displayed a lower affinity (K(i) 675 nM). The SARs developed from the new compounds, together with those collected from our previous studies, confirmed the hypothesis of different binding modes for 5-substituted and 5-unsubstituted indoles, suggesting that the shape of the lipophilic pocket L(1) (notation in accordance with Cook's BzR topological model) is asymmetric and highlighted the stereoelectronic and conformational properties of the amide side chain required for high potency. Several of the new indoles showed selectivity for the alpha(1)beta(2)gamma(2) subtype compared with the alpha(3)beta(2)gamma(2) and alpha(5)beta(3)gamma(2) subtypes (e.g.: 4t and 7c bind to these three BzR isoforms with K(i) values of 14 nM, 283 nM, 239 nM, and 9 nM, 1960 nM, 95 nM, respectively). The GABA ratios close to unity exhibited by all the tested compounds on each BzR subtype were predictive of an efficacy profile typical of antagonists.
|
Binding affinity was determined by displacement of [3H]flumazenil from rat cortex homogenates
|
Rattus norvegicus
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABA(A) receptor.
Year : 2002
Volume : 45
Issue : 23
First Page : 5043
Last Page : 5051
Authors : Albaugh PA, Marshall L, Gregory J, White G, Hutchison A, Ross PC, Gallagher DW, Tallman JF, Crago M, Cassella JV.
Abstract : Benzodiazepines are allosteric modulators of the GABA(A) receptor. The traditionally prescribed benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification of receptor subtypes, we set out to discover selective agents with the anticipation that these agents would have superior therapeutic potential. Herein, we describe the synthesis and biological evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-ones and disclose that these compounds exhibit functional selectivity at the benzodiazepine receptor of GABA(A) receptor subtypes. The alpha(2)/alpha(3)-selective partial agonist 42 exhibited potent in vivo activity.
|
Binding affinity for rat GABA-A receptor alpha-1-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
19.0
nM
|
|
Journal : J. Med. Chem.
Title : Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor.
Year : 1994
Volume : 37
Issue : 26
First Page : 4576
Last Page : 4580
Authors : Wieland HA, Lüddens H.
Abstract : Benzodiazepines (BZ) exert their effects through GABAA receptors, which belong to the superfamily of ligand-gated ion channels. Coexpression of recombinant alpha, beta, and gamma subunits in a cell culture system mimics the BZ binding sites. The alpha variants largely determine the nature of the BZ binding site in such alpha i beta j gamma k heteromultimers (i = 1-6; j = 1-3; k = 1-3). Notably, the alpha 1 and alpha 6 variants confer high and low affinity for BZ agonists to the resulting receptor subtype, respectively. Glycine/glutamate and histidine/arginine positions in the alpha subunits of alpha x beta 2 gamma 2 receptors are involved in BZ I versus BZ II type selectivity. We now identify four amino acids in alpha 6 which together increase the affinity of the mutant alpha x beta 2 gamma 2 receptor for classical BZ receptor agonists above the level seen for any wild-type GABAA/BZ receptor. The most pronounced effect was due to an isoleucine to valine exchange. It simultaneously decreased the affinity for the BZ partial inverse agonist Ro 15-4513 20-fold and increased the affinity for diazepam 4-fold. The four amino acid residues stretch over most part of the N-terminal extracellular domain of the alpha subunit, suggesting that amino acids distant in the primary sequence form the BZ binding pocket.
|
Binding affinity measured using LtK- cell membranes expressing GABA alpha-1-beta-3-gamma-2 receptor
|
None
|
26.7
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC) and the full agonist 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and recombinant GABAA receptors.
Year : 1998
Volume : 41
Issue : 14
First Page : 2537
Last Page : 2552
Authors : Cox ED, Diaz-Arauzo H, Huang Q, Reddy MS, Ma C, Harris B, McKernan R, Skolnick P, Cook JM.
Abstract : A pharmacophore and an alignment rule have previously been reported for BzR agonist ligands. The design and synthesis of 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC, 24, IC50 = 8.1 nM) was based on this pharmacophore. When evaluated in vivo this ligand exhibited anticonvulsant/anxiolytic activity but was devoid of the muscle relaxant/ataxic effects of "classical" 1,4-benzodiazepines (i.e., diazepam). Significantly, 6-PBC 24 also reversed diazepam-induced muscle relaxation in mice. The 3-substituted analogues 40-46 and 48 of 6-PBC 24 and Zk 93423 27(IC50 = 1 nM) were synthesized and evaluated in vitro to determine what affect these modifications would have on the binding affinity at recombinant BzR subtypes. With the exception of the 3-amino ligands 40 and 41, all the beta-carbolines were found to exhibit high binding affinity at BzR sites. The 3-propyl ether derivative 45 was also evaluated in vivo and found to be devoid of any proconvulsant or anticonvulsant activity at doses up to 40 mg/kg. The 6-(1-naphthylmethyloxy) and 6-octyloxy analogues 25, 26, 28, and 29 of 6-PBC 24 were synthesized to further evaluate the proposed alignment of agonists vs inverse agonists in the pharmacophore of the BzR. In addition, ligands 26 and 29 were designed to probe the dimensions of lipophilic pocket L3 at the agonist site. The activity of 29 was evaluated in vivo; however, this analogue elicited no pharmacological effects at doses up to 80 mg/kg. These and other related beta-carbolines were also examined in five recombinant GABAA receptor subtypes. Ligands 52-61 all exhibited moderate to high affinity at GABAA receptors containing alpha1 subunits. These ligands will be useful in further defining the pharmacophore at alpha1 beta3 gamma2 receptors.
|
Potentiation of GABA-evoked Cl- currents in Xenopus oocytes expressing human alpha-2-beta-2-gamma-2 subunits
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and binding affinity of 2-phenylimidazo[1,2-alpha]pyridine derivatives for both central and peripheral benzodiazepine receptors. A new series of high-affinity and selective ligands for the peripheral type.
Year : 1997
Volume : 40
Issue : 19
First Page : 3109
Last Page : 3118
Authors : Trapani G, Franco M, Ricciardi L, Latrofa A, Genchi G, Sanna E, Tuveri F, Cagetti E, Biggio G, Liso G.
Abstract : A number of 6-substituted or 6,8-disubstituted alkyl 2-phenylimidazo[1,2-alpha]pyridine-3-carboxylates 5a-h, -acetates 5i-s, 6a-g, and -propionates 5t, 6h and of N,N-dialkyl-2-phenylimidazo[1,2-alpha]pyridine-3-carboxamides 7a-d,-acetamides 7e-t or -propionamide 7u were prepared following new synthetic methods, and their affinities for both the central (CBR) and the peripheral (PBR) benzodiazepine receptors evaluated. The compounds of the ester series displayed low affinity for both receptor types. Conversely, most of N,N-dialkyl(2-phenylimidazo[1,2-alpha]pyridin-3-yl)acetamides 7e-t proved to possess high affinity and selectivity for CBR or PBR depending on the nature of substituents at C(6)- and/or C(8) on the heterocyclic ring system. In particular, the 6-substituted compounds 7f-n displayed ratios of IC50 values (IC50(CBR)/IC50(PBR)) ranging from 0.32 (7m) to 232 (7k), while the 6,8-disubstituted compounds 7o-t were more than 1000-fold more selective for PBR versus CBR. Compounds 7f,m were examined in several different benzodiazepine receptor subtypes. Expression of specific GABAA, receptor subunit assemblies in Xenopus oocytes was utilized to evaluate functionally both the efficacy and potency of the positive modulation of GABA-evoked Cl- currents by 7f and 7m in comparison with Zolpidem. The rank order of potencies of these drugs was 7f (EC50 = 3.2 x 10(-8) M) > Zolpidem (EC50 = 3.6 x 10(-8) M) > 7m (EC50 = 2.2 x 10(-7) M). The actions of these compounds were also tested on alpha 2 beta 2 gamma 2s, receptors. However, the EC50 of these compounds was increased, compared to alpha 1 beta 2 gamma 2s receptors, by 30-, 4-, and 5-fold for 7m, 7f, and Zolpidem, respectively. Finally, these compounds were almost completely devoid of activity at receptors containing the alpha 5 subunit.
|
Binding affinity measured using LtK- cell membranes expressing GABA alpha-2-beta-3-gamma-2 receptor
|
None
|
156.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC) and the full agonist 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and recombinant GABAA receptors.
Year : 1998
Volume : 41
Issue : 14
First Page : 2537
Last Page : 2552
Authors : Cox ED, Diaz-Arauzo H, Huang Q, Reddy MS, Ma C, Harris B, McKernan R, Skolnick P, Cook JM.
Abstract : A pharmacophore and an alignment rule have previously been reported for BzR agonist ligands. The design and synthesis of 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC, 24, IC50 = 8.1 nM) was based on this pharmacophore. When evaluated in vivo this ligand exhibited anticonvulsant/anxiolytic activity but was devoid of the muscle relaxant/ataxic effects of "classical" 1,4-benzodiazepines (i.e., diazepam). Significantly, 6-PBC 24 also reversed diazepam-induced muscle relaxation in mice. The 3-substituted analogues 40-46 and 48 of 6-PBC 24 and Zk 93423 27(IC50 = 1 nM) were synthesized and evaluated in vitro to determine what affect these modifications would have on the binding affinity at recombinant BzR subtypes. With the exception of the 3-amino ligands 40 and 41, all the beta-carbolines were found to exhibit high binding affinity at BzR sites. The 3-propyl ether derivative 45 was also evaluated in vivo and found to be devoid of any proconvulsant or anticonvulsant activity at doses up to 40 mg/kg. The 6-(1-naphthylmethyloxy) and 6-octyloxy analogues 25, 26, 28, and 29 of 6-PBC 24 were synthesized to further evaluate the proposed alignment of agonists vs inverse agonists in the pharmacophore of the BzR. In addition, ligands 26 and 29 were designed to probe the dimensions of lipophilic pocket L3 at the agonist site. The activity of 29 was evaluated in vivo; however, this analogue elicited no pharmacological effects at doses up to 80 mg/kg. These and other related beta-carbolines were also examined in five recombinant GABAA receptor subtypes. Ligands 52-61 all exhibited moderate to high affinity at GABAA receptors containing alpha1 subunits. These ligands will be useful in further defining the pharmacophore at alpha1 beta3 gamma2 receptors.
|
Binding affinity for rat GABA-A receptor alpha-3-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor.
Year : 1994
Volume : 37
Issue : 26
First Page : 4576
Last Page : 4580
Authors : Wieland HA, Lüddens H.
Abstract : Benzodiazepines (BZ) exert their effects through GABAA receptors, which belong to the superfamily of ligand-gated ion channels. Coexpression of recombinant alpha, beta, and gamma subunits in a cell culture system mimics the BZ binding sites. The alpha variants largely determine the nature of the BZ binding site in such alpha i beta j gamma k heteromultimers (i = 1-6; j = 1-3; k = 1-3). Notably, the alpha 1 and alpha 6 variants confer high and low affinity for BZ agonists to the resulting receptor subtype, respectively. Glycine/glutamate and histidine/arginine positions in the alpha subunits of alpha x beta 2 gamma 2 receptors are involved in BZ I versus BZ II type selectivity. We now identify four amino acids in alpha 6 which together increase the affinity of the mutant alpha x beta 2 gamma 2 receptor for classical BZ receptor agonists above the level seen for any wild-type GABAA/BZ receptor. The most pronounced effect was due to an isoleucine to valine exchange. It simultaneously decreased the affinity for the BZ partial inverse agonist Ro 15-4513 20-fold and increased the affinity for diazepam 4-fold. The four amino acid residues stretch over most part of the N-terminal extracellular domain of the alpha subunit, suggesting that amino acids distant in the primary sequence form the BZ binding pocket.
|
Binding affinity measured using LtK- cell membranes expressing GABA alpha-3-beta-3-gamma-2 receptor
|
None
|
383.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC) and the full agonist 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and recombinant GABAA receptors.
Year : 1998
Volume : 41
Issue : 14
First Page : 2537
Last Page : 2552
Authors : Cox ED, Diaz-Arauzo H, Huang Q, Reddy MS, Ma C, Harris B, McKernan R, Skolnick P, Cook JM.
Abstract : A pharmacophore and an alignment rule have previously been reported for BzR agonist ligands. The design and synthesis of 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC, 24, IC50 = 8.1 nM) was based on this pharmacophore. When evaluated in vivo this ligand exhibited anticonvulsant/anxiolytic activity but was devoid of the muscle relaxant/ataxic effects of "classical" 1,4-benzodiazepines (i.e., diazepam). Significantly, 6-PBC 24 also reversed diazepam-induced muscle relaxation in mice. The 3-substituted analogues 40-46 and 48 of 6-PBC 24 and Zk 93423 27(IC50 = 1 nM) were synthesized and evaluated in vitro to determine what affect these modifications would have on the binding affinity at recombinant BzR subtypes. With the exception of the 3-amino ligands 40 and 41, all the beta-carbolines were found to exhibit high binding affinity at BzR sites. The 3-propyl ether derivative 45 was also evaluated in vivo and found to be devoid of any proconvulsant or anticonvulsant activity at doses up to 40 mg/kg. The 6-(1-naphthylmethyloxy) and 6-octyloxy analogues 25, 26, 28, and 29 of 6-PBC 24 were synthesized to further evaluate the proposed alignment of agonists vs inverse agonists in the pharmacophore of the BzR. In addition, ligands 26 and 29 were designed to probe the dimensions of lipophilic pocket L3 at the agonist site. The activity of 29 was evaluated in vivo; however, this analogue elicited no pharmacological effects at doses up to 80 mg/kg. These and other related beta-carbolines were also examined in five recombinant GABAA receptor subtypes. Ligands 52-61 all exhibited moderate to high affinity at GABAA receptors containing alpha1 subunits. These ligands will be useful in further defining the pharmacophore at alpha1 beta3 gamma2 receptors.
|
Binding affinity for mutant rat GABA-A receptor alpha-4-(his)-beta-2-gamma-2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
76.0
nM
|
|
Journal : J. Med. Chem.
Title : Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor.
Year : 1994
Volume : 37
Issue : 26
First Page : 4576
Last Page : 4580
Authors : Wieland HA, Lüddens H.
Abstract : Benzodiazepines (BZ) exert their effects through GABAA receptors, which belong to the superfamily of ligand-gated ion channels. Coexpression of recombinant alpha, beta, and gamma subunits in a cell culture system mimics the BZ binding sites. The alpha variants largely determine the nature of the BZ binding site in such alpha i beta j gamma k heteromultimers (i = 1-6; j = 1-3; k = 1-3). Notably, the alpha 1 and alpha 6 variants confer high and low affinity for BZ agonists to the resulting receptor subtype, respectively. Glycine/glutamate and histidine/arginine positions in the alpha subunits of alpha x beta 2 gamma 2 receptors are involved in BZ I versus BZ II type selectivity. We now identify four amino acids in alpha 6 which together increase the affinity of the mutant alpha x beta 2 gamma 2 receptor for classical BZ receptor agonists above the level seen for any wild-type GABAA/BZ receptor. The most pronounced effect was due to an isoleucine to valine exchange. It simultaneously decreased the affinity for the BZ partial inverse agonist Ro 15-4513 20-fold and increased the affinity for diazepam 4-fold. The four amino acid residues stretch over most part of the N-terminal extracellular domain of the alpha subunit, suggesting that amino acids distant in the primary sequence form the BZ binding pocket.
|
Binding affinity for mutant rat GABA-A receptor alpha-6-(his,thr,gly)beta2gamma2 subunits expressed in HEK293 cells
|
Rattus norvegicus
|
980.0
nM
|
|
Journal : J. Med. Chem.
Title : Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor.
Year : 1994
Volume : 37
Issue : 26
First Page : 4576
Last Page : 4580
Authors : Wieland HA, Lüddens H.
Abstract : Benzodiazepines (BZ) exert their effects through GABAA receptors, which belong to the superfamily of ligand-gated ion channels. Coexpression of recombinant alpha, beta, and gamma subunits in a cell culture system mimics the BZ binding sites. The alpha variants largely determine the nature of the BZ binding site in such alpha i beta j gamma k heteromultimers (i = 1-6; j = 1-3; k = 1-3). Notably, the alpha 1 and alpha 6 variants confer high and low affinity for BZ agonists to the resulting receptor subtype, respectively. Glycine/glutamate and histidine/arginine positions in the alpha subunits of alpha x beta 2 gamma 2 receptors are involved in BZ I versus BZ II type selectivity. We now identify four amino acids in alpha 6 which together increase the affinity of the mutant alpha x beta 2 gamma 2 receptor for classical BZ receptor agonists above the level seen for any wild-type GABAA/BZ receptor. The most pronounced effect was due to an isoleucine to valine exchange. It simultaneously decreased the affinity for the BZ partial inverse agonist Ro 15-4513 20-fold and increased the affinity for diazepam 4-fold. The four amino acid residues stretch over most part of the N-terminal extracellular domain of the alpha subunit, suggesting that amino acids distant in the primary sequence form the BZ binding pocket.
|
Effective concentration against gamma-aminobutyric acid (GABA) A receptor, alpha 1
|
Xenopus laevis
|
198.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABA(A) receptor.
Year : 2002
Volume : 45
Issue : 23
First Page : 5043
Last Page : 5051
Authors : Albaugh PA, Marshall L, Gregory J, White G, Hutchison A, Ross PC, Gallagher DW, Tallman JF, Crago M, Cassella JV.
Abstract : Benzodiazepines are allosteric modulators of the GABA(A) receptor. The traditionally prescribed benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification of receptor subtypes, we set out to discover selective agents with the anticipation that these agents would have superior therapeutic potential. Herein, we describe the synthesis and biological evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-ones and disclose that these compounds exhibit functional selectivity at the benzodiazepine receptor of GABA(A) receptor subtypes. The alpha(2)/alpha(3)-selective partial agonist 42 exhibited potent in vivo activity.
|
Inhibition of [3H]Ro-151788 binding to recombinant human gamma-aminobutyric acid A receptor alpha-2-beta-3-gamma-2 subtype expressed in L (tk-) cells
|
Homo sapiens
|
103.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit.
Year : 2005
Volume : 48
Issue : 5
First Page : 1367
Last Page : 1383
Authors : Russell MG, Carling RW, Atack JR, Bromidge FA, Cook SM, Hunt P, Isted C, Lucas M, McKernan RM, Mitchinson A, Moore KW, Narquizian R, Macaulay AJ, Thomas D, Thompson SA, Wafford KA, Castro JL.
Abstract : We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
|
Inhibition of [3H]Ro-151788 binding to recombinant human gamma-aminobutyric-acid A receptor alpha-1-beta-3-gamma-2 subtype expressed in L (tk-) cells
|
Homo sapiens
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit.
Year : 2005
Volume : 48
Issue : 5
First Page : 1367
Last Page : 1383
Authors : Russell MG, Carling RW, Atack JR, Bromidge FA, Cook SM, Hunt P, Isted C, Lucas M, McKernan RM, Mitchinson A, Moore KW, Narquizian R, Macaulay AJ, Thomas D, Thompson SA, Wafford KA, Castro JL.
Abstract : We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
|
Inhibition of [3H]Ro-151788 binding to recombinant human gamma-aminobutyric-acid A receptor alpha-3-beta-3-gamma-2 subtype expressed in L (tk-) cells
|
Homo sapiens
|
246.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit.
Year : 2005
Volume : 48
Issue : 5
First Page : 1367
Last Page : 1383
Authors : Russell MG, Carling RW, Atack JR, Bromidge FA, Cook SM, Hunt P, Isted C, Lucas M, McKernan RM, Mitchinson A, Moore KW, Narquizian R, Macaulay AJ, Thomas D, Thompson SA, Wafford KA, Castro JL.
Abstract : We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
|
Displacement of [3H]flumazenil from rat GABA-A Gamma-aminobutyric acid A receptor alpha-1-beta-2-gamma-2 expressed in HEK293 cells
|
Rattus norvegicus
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : High affinity central benzodiazepine receptor ligands: synthesis and biological evaluation of a series of phenyltriazolobenzotriazindione derivatives.
Year : 2005
Volume : 48
Issue : 8
First Page : 2936
Last Page : 2943
Authors : Primofiore G, Da Settimo F, Taliani S, Salerno S, Novellino E, Greco G, Cosimelli B, Besnard F, Costa B, Montali M, Martini C.
Abstract : A series of 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones (PTBTs), VII, were prepared and tested at the central benzodiazepine receptor (BzR). The skeleton of these compounds was designed by formally combining the N-C=O moieties of the known BzR ligands, triazoloquinoxalines (IV) and triazinobenzimidazoles (ATBIs) (VI). Most of the PTBTs displayed submicromolar/nanomolar potency at the BzR. The 9-chloro derivatives (45-49) were generally found to be more potent than their 9-unsubstituted counterparts (37-44). Compound 45 turned out to be the most potent of the PTBTs (K(i) 2.8 nM). A subset of compounds (37, 42, 45, 49), when tested for their affinity on recombinant rat alpha1beta2gamma2, alpha2beta2gamma2, and alpha5beta3gamma2 GABA(A)/Bz receptor subtypes, showed enhanced affinities for the alpha1beta2gamma2 isoform, with compounds 45 and 49 exhibiting the highest selectivity. Moreover, compounds 45 and 49 were found to display a full agonist efficacy profile at alpha1 and alpha2 receptor subtypes, and an antagonist efficacy at alpha5-containing receptors.
|
Displacement of [3H]flumazenil from rat GABA-A Gamma-aminobutyric acid A receptor alpha-2-beta-2-gamma-2 expressed in HEK293 cells
|
Rattus norvegicus
|
765.0
nM
|
|
Journal : J. Med. Chem.
Title : High affinity central benzodiazepine receptor ligands: synthesis and biological evaluation of a series of phenyltriazolobenzotriazindione derivatives.
Year : 2005
Volume : 48
Issue : 8
First Page : 2936
Last Page : 2943
Authors : Primofiore G, Da Settimo F, Taliani S, Salerno S, Novellino E, Greco G, Cosimelli B, Besnard F, Costa B, Montali M, Martini C.
Abstract : A series of 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones (PTBTs), VII, were prepared and tested at the central benzodiazepine receptor (BzR). The skeleton of these compounds was designed by formally combining the N-C=O moieties of the known BzR ligands, triazoloquinoxalines (IV) and triazinobenzimidazoles (ATBIs) (VI). Most of the PTBTs displayed submicromolar/nanomolar potency at the BzR. The 9-chloro derivatives (45-49) were generally found to be more potent than their 9-unsubstituted counterparts (37-44). Compound 45 turned out to be the most potent of the PTBTs (K(i) 2.8 nM). A subset of compounds (37, 42, 45, 49), when tested for their affinity on recombinant rat alpha1beta2gamma2, alpha2beta2gamma2, and alpha5beta3gamma2 GABA(A)/Bz receptor subtypes, showed enhanced affinities for the alpha1beta2gamma2 isoform, with compounds 45 and 49 exhibiting the highest selectivity. Moreover, compounds 45 and 49 were found to display a full agonist efficacy profile at alpha1 and alpha2 receptor subtypes, and an antagonist efficacy at alpha5-containing receptors.
|
Inhibition of [3H]flumazenil binding to rat Gamma-aminobutyric acid A GABA-A receptor alpha-5-beta-3-gamma-2 expressed in HEK293 cells
|
Rattus norvegicus
|
35.0
%
|
|
Journal : J. Med. Chem.
Title : High affinity central benzodiazepine receptor ligands: synthesis and biological evaluation of a series of phenyltriazolobenzotriazindione derivatives.
Year : 2005
Volume : 48
Issue : 8
First Page : 2936
Last Page : 2943
Authors : Primofiore G, Da Settimo F, Taliani S, Salerno S, Novellino E, Greco G, Cosimelli B, Besnard F, Costa B, Montali M, Martini C.
Abstract : A series of 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones (PTBTs), VII, were prepared and tested at the central benzodiazepine receptor (BzR). The skeleton of these compounds was designed by formally combining the N-C=O moieties of the known BzR ligands, triazoloquinoxalines (IV) and triazinobenzimidazoles (ATBIs) (VI). Most of the PTBTs displayed submicromolar/nanomolar potency at the BzR. The 9-chloro derivatives (45-49) were generally found to be more potent than their 9-unsubstituted counterparts (37-44). Compound 45 turned out to be the most potent of the PTBTs (K(i) 2.8 nM). A subset of compounds (37, 42, 45, 49), when tested for their affinity on recombinant rat alpha1beta2gamma2, alpha2beta2gamma2, and alpha5beta3gamma2 GABA(A)/Bz receptor subtypes, showed enhanced affinities for the alpha1beta2gamma2 isoform, with compounds 45 and 49 exhibiting the highest selectivity. Moreover, compounds 45 and 49 were found to display a full agonist efficacy profile at alpha1 and alpha2 receptor subtypes, and an antagonist efficacy at alpha5-containing receptors.
|
Binding affinity for rat alpha-1 beta2/3 gamma2 GABA A / BzR receptor
|
Rattus norvegicus
|
26.7
nM
|
|
Journal : J. Med. Chem.
Title : A novel selective GABA(A) alpha1 receptor agonist displaying sedative and anxiolytic-like properties in rodents.
Year : 2005
Volume : 48
Issue : 21
First Page : 6756
Last Page : 6760
Authors : Selleri S, Bruni F, Costagli C, Costanzo A, Guerrini G, Ciciani G, Gratteri P, Besnard F, Costa B, Montali M, Martini C, Fohlin J, De Siena G, Aiello PM.
Abstract : In our pursuit to identify selective ligands for Bz/GABA(A) receptor subtypes, a novel pyrazolo[1,5-a]pyrimidine derivative (4), the azaisostere of zolpidem, was synthesized and evaluated in vitro on bovine brain homogenate and on recombinant benzodiazepine receptors (alphaxbeta2/3gamma2, x = 1-3, 5) expressed in HEK293 cells. Compound 4 displayed affinity only for alpha1beta2gamma2 subtype (K(i) = 31 nM), and in an in-depth, in vivo study it revealed sedative and anxiolytic-like properties without any amnesic and myorelaxant effects in rodents.
|
Binding affinity for rat alpha2 beta2/3 gamma2 GABA-A/BzR receptor
|
Rattus norvegicus
|
156.0
nM
|
|
Journal : J. Med. Chem.
Title : A novel selective GABA(A) alpha1 receptor agonist displaying sedative and anxiolytic-like properties in rodents.
Year : 2005
Volume : 48
Issue : 21
First Page : 6756
Last Page : 6760
Authors : Selleri S, Bruni F, Costagli C, Costanzo A, Guerrini G, Ciciani G, Gratteri P, Besnard F, Costa B, Montali M, Martini C, Fohlin J, De Siena G, Aiello PM.
Abstract : In our pursuit to identify selective ligands for Bz/GABA(A) receptor subtypes, a novel pyrazolo[1,5-a]pyrimidine derivative (4), the azaisostere of zolpidem, was synthesized and evaluated in vitro on bovine brain homogenate and on recombinant benzodiazepine receptors (alphaxbeta2/3gamma2, x = 1-3, 5) expressed in HEK293 cells. Compound 4 displayed affinity only for alpha1beta2gamma2 subtype (K(i) = 31 nM), and in an in-depth, in vivo study it revealed sedative and anxiolytic-like properties without any amnesic and myorelaxant effects in rodents.
|
Binding affinity for rat alpha-3 beta2/3 gamma2 GABA-A/BzR receptor
|
Rattus norvegicus
|
383.0
nM
|
|
Journal : J. Med. Chem.
Title : A novel selective GABA(A) alpha1 receptor agonist displaying sedative and anxiolytic-like properties in rodents.
Year : 2005
Volume : 48
Issue : 21
First Page : 6756
Last Page : 6760
Authors : Selleri S, Bruni F, Costagli C, Costanzo A, Guerrini G, Ciciani G, Gratteri P, Besnard F, Costa B, Montali M, Martini C, Fohlin J, De Siena G, Aiello PM.
Abstract : In our pursuit to identify selective ligands for Bz/GABA(A) receptor subtypes, a novel pyrazolo[1,5-a]pyrimidine derivative (4), the azaisostere of zolpidem, was synthesized and evaluated in vitro on bovine brain homogenate and on recombinant benzodiazepine receptors (alphaxbeta2/3gamma2, x = 1-3, 5) expressed in HEK293 cells. Compound 4 displayed affinity only for alpha1beta2gamma2 subtype (K(i) = 31 nM), and in an in-depth, in vivo study it revealed sedative and anxiolytic-like properties without any amnesic and myorelaxant effects in rodents.
|
Displacement of [3H]Flumazenil from human GABA-Aalpha1 receptor plus beta-2-gamma-2 expressed in HEK293 cells
|
Homo sapiens
|
53.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-quinolone derivatives: high-affinity ligands at the benzodiazepine site of brain GABA A receptors. synthesis, pharmacology, and pharmacophore modeling.
Year : 2006
Volume : 49
Issue : 8
First Page : 2526
Last Page : 2533
Authors : Lager E, Andersson P, Nilsson J, Pettersson I, Nielsen EØ, Nielsen M, Sterner O, Liljefors T.
Abstract : The 3-ethoxycarbonyl-4-quinolone compound 1 has previously been identified via a database search as an interesting lead compound for ligand binding at the benzodiazepine site of GABA(A) receptors (Kahnberg et al. J. Mol. Graphics Modelling 2004, 23, 253-261). Pharmacophore-guided optimization of this lead compound yielded a number of high-affinity ligands for the benzodiazepine site including compounds 20 and 23-25 displaying sub-nanomolar affinities. A few of the compounds have been tested on the alpha(1)beta(2)gamma(2S) and alpha(3)beta(2)gamma(2S) GABA(A) receptor subtypes, and two of the compounds (5 and 19) display selectivity for alpha(1)- versus alpha(3)-containing receptors by a factor of 22 and 27, respectively. This selectivity for alpha(1)beta(2)gamma(2S) is in the same range as that for the well-known alpha(1) subunit selective compound zolpidem.
|
Displacement of [3H]flumazenil from rat GABA-Aalpha1 receptor plus beta-2-gamma-2 in HEK293 cells
|
Rattus norvegicus
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Refinement of the benzodiazepine receptor site topology by structure-activity relationships of new N-(heteroarylmethyl)indol-3-ylglyoxylamides.
Year : 2006
Volume : 49
Issue : 8
First Page : 2489
Last Page : 2495
Authors : Primofiore G, Da Settimo F, Marini AM, Taliani S, La Motta C, Simorini F, Novellino E, Greco G, Cosimelli B, Ehlardo M, Sala A, Besnard F, Montali M, Martini C.
Abstract : N-(heteroarylmethyl)indol-3-ylglyoxylamides (1-26) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR) to probe the hydrogen bonding properties of the so-called S(1) site of the BzR by means of suitable heterocyclic side chains. SARs were developed in light of our hypothesis of binding modes A and B. Pyrrole and furan derivatives adopting mode A (2, 8, 10, 20, 22) turned out to be more potent (K(i) values < 35 nM) than their analogues lacking hydrogen bonding heterocyclic side chains. These data suggest that the most potent indoles interact with a hydrogen bond acceptor/donor (HBA/D) group located within the S(1) site of the BzR. Compounds 1, 2, 8, 19, 20, and 22, tested at recombinant rat alpha(1)beta(2)gamma(2), alpha(2)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzRs, elicited selectivity for the alpha(1)beta(2)gamma(2) isoform. On the basis of published mutagenesis studies and the present SARs, we speculate that the S(1) HBA/D group might be identified as the hydroxyl of alpha(1)-Tyr209 or of other neighboring amino acids.
|
Displacement of [3H]flumazenil from rat GABA-Aalpha2 receptor plus beta-2-gamma-2 in HEK293 cells
|
Rattus norvegicus
|
765.0
nM
|
|
Journal : J. Med. Chem.
Title : Refinement of the benzodiazepine receptor site topology by structure-activity relationships of new N-(heteroarylmethyl)indol-3-ylglyoxylamides.
Year : 2006
Volume : 49
Issue : 8
First Page : 2489
Last Page : 2495
Authors : Primofiore G, Da Settimo F, Marini AM, Taliani S, La Motta C, Simorini F, Novellino E, Greco G, Cosimelli B, Ehlardo M, Sala A, Besnard F, Montali M, Martini C.
Abstract : N-(heteroarylmethyl)indol-3-ylglyoxylamides (1-26) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR) to probe the hydrogen bonding properties of the so-called S(1) site of the BzR by means of suitable heterocyclic side chains. SARs were developed in light of our hypothesis of binding modes A and B. Pyrrole and furan derivatives adopting mode A (2, 8, 10, 20, 22) turned out to be more potent (K(i) values < 35 nM) than their analogues lacking hydrogen bonding heterocyclic side chains. These data suggest that the most potent indoles interact with a hydrogen bond acceptor/donor (HBA/D) group located within the S(1) site of the BzR. Compounds 1, 2, 8, 19, 20, and 22, tested at recombinant rat alpha(1)beta(2)gamma(2), alpha(2)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzRs, elicited selectivity for the alpha(1)beta(2)gamma(2) isoform. On the basis of published mutagenesis studies and the present SARs, we speculate that the S(1) HBA/D group might be identified as the hydroxyl of alpha(1)-Tyr209 or of other neighboring amino acids.
|
Inhibition of [3H]flumazenil binding to rat GABA-Aalpha5 receptor plus beta-3-gamma-2 at 10 uM in HEK293 cells
|
Rattus norvegicus
|
35.0
%
|
|
Journal : J. Med. Chem.
Title : Refinement of the benzodiazepine receptor site topology by structure-activity relationships of new N-(heteroarylmethyl)indol-3-ylglyoxylamides.
Year : 2006
Volume : 49
Issue : 8
First Page : 2489
Last Page : 2495
Authors : Primofiore G, Da Settimo F, Marini AM, Taliani S, La Motta C, Simorini F, Novellino E, Greco G, Cosimelli B, Ehlardo M, Sala A, Besnard F, Montali M, Martini C.
Abstract : N-(heteroarylmethyl)indol-3-ylglyoxylamides (1-26) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR) to probe the hydrogen bonding properties of the so-called S(1) site of the BzR by means of suitable heterocyclic side chains. SARs were developed in light of our hypothesis of binding modes A and B. Pyrrole and furan derivatives adopting mode A (2, 8, 10, 20, 22) turned out to be more potent (K(i) values < 35 nM) than their analogues lacking hydrogen bonding heterocyclic side chains. These data suggest that the most potent indoles interact with a hydrogen bond acceptor/donor (HBA/D) group located within the S(1) site of the BzR. Compounds 1, 2, 8, 19, 20, and 22, tested at recombinant rat alpha(1)beta(2)gamma(2), alpha(2)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzRs, elicited selectivity for the alpha(1)beta(2)gamma(2) isoform. On the basis of published mutagenesis studies and the present SARs, we speculate that the S(1) HBA/D group might be identified as the hydroxyl of alpha(1)-Tyr209 or of other neighboring amino acids.
|
Displacement of [3H]flumazenil from rat GABAA alpha-1-beta-2-gamma-2 expressed in HEK293 cells
|
Rattus norvegicus
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel N-substituted indol-3-ylglyoxylamides probing the LDi and L1/L2 lipophilic regions of the benzodiazepine receptor site in search for subtype-selective ligands.
Year : 2007
Volume : 50
Issue : 7
First Page : 1627
Last Page : 1634
Authors : Primofiore G, Taliani S, Da Settimo F, Marini AM, La Motta C, Simorini F, Patrizi MP, Sergianni V, Novellino E, Greco G, Cosimelli B, Calderone V, Montali M, Besnard F, Martini C.
Abstract : Novel N-substituted indol-3-ylglyoxylamides (10-37) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR). In an effort to achieve affinity-based selectivity among BzR subtypes, these compounds were designed to probe the LDi and L2 lipophilic regions. Taking the alpha1-selective benzylindolylglyoxylamides Ia and Ib as leads, we varied the substituent on the benzylamide phenyl ring (compounds 10-23) or replaced the benzyl moiety with alkyl groups (compounds 24-37). The above structural changes gave no shift of selectivity from the alpha1 toward the alpha2 or alpha5 subtypes, thus confirming that a ligand which occupies the LDi region probably exhibits alpha1 selectivity, despite its interactions with other lipophilic areas in the receptor binding cleft. Compound 11 (N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide), which selectively binds with a full agonist efficacy at the alpha1 receptor subtype and displays sedative action, can be regarded as an interesting potential zolpidem-like sedative-hypnotic agent.
|
Displacement of [3H]flumazenil from rat GABAA alpha-2-beta-2-gamma-2 expressed in HEK293 cells
|
Rattus norvegicus
|
765.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel N-substituted indol-3-ylglyoxylamides probing the LDi and L1/L2 lipophilic regions of the benzodiazepine receptor site in search for subtype-selective ligands.
Year : 2007
Volume : 50
Issue : 7
First Page : 1627
Last Page : 1634
Authors : Primofiore G, Taliani S, Da Settimo F, Marini AM, La Motta C, Simorini F, Patrizi MP, Sergianni V, Novellino E, Greco G, Cosimelli B, Calderone V, Montali M, Besnard F, Martini C.
Abstract : Novel N-substituted indol-3-ylglyoxylamides (10-37) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR). In an effort to achieve affinity-based selectivity among BzR subtypes, these compounds were designed to probe the LDi and L2 lipophilic regions. Taking the alpha1-selective benzylindolylglyoxylamides Ia and Ib as leads, we varied the substituent on the benzylamide phenyl ring (compounds 10-23) or replaced the benzyl moiety with alkyl groups (compounds 24-37). The above structural changes gave no shift of selectivity from the alpha1 toward the alpha2 or alpha5 subtypes, thus confirming that a ligand which occupies the LDi region probably exhibits alpha1 selectivity, despite its interactions with other lipophilic areas in the receptor binding cleft. Compound 11 (N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide), which selectively binds with a full agonist efficacy at the alpha1 receptor subtype and displays sedative action, can be regarded as an interesting potential zolpidem-like sedative-hypnotic agent.
|
Displacement of [3H]flumazenil from rat GABAA alpha-5-beta-3-gamma-2 expressed in HEK293 cells at 10 uM
|
Rattus norvegicus
|
35.0
%
|
|
Journal : J. Med. Chem.
Title : Novel N-substituted indol-3-ylglyoxylamides probing the LDi and L1/L2 lipophilic regions of the benzodiazepine receptor site in search for subtype-selective ligands.
Year : 2007
Volume : 50
Issue : 7
First Page : 1627
Last Page : 1634
Authors : Primofiore G, Taliani S, Da Settimo F, Marini AM, La Motta C, Simorini F, Patrizi MP, Sergianni V, Novellino E, Greco G, Cosimelli B, Calderone V, Montali M, Besnard F, Martini C.
Abstract : Novel N-substituted indol-3-ylglyoxylamides (10-37) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR). In an effort to achieve affinity-based selectivity among BzR subtypes, these compounds were designed to probe the LDi and L2 lipophilic regions. Taking the alpha1-selective benzylindolylglyoxylamides Ia and Ib as leads, we varied the substituent on the benzylamide phenyl ring (compounds 10-23) or replaced the benzyl moiety with alkyl groups (compounds 24-37). The above structural changes gave no shift of selectivity from the alpha1 toward the alpha2 or alpha5 subtypes, thus confirming that a ligand which occupies the LDi region probably exhibits alpha1 selectivity, despite its interactions with other lipophilic areas in the receptor binding cleft. Compound 11 (N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide), which selectively binds with a full agonist efficacy at the alpha1 receptor subtype and displays sedative action, can be regarded as an interesting potential zolpidem-like sedative-hypnotic agent.
|
Displacement of [3H]Ro 15-1788 from human recombinant GABAA alpha-1-beta-3-gamma-2 receptor expressed in L(tk-) cells
|
Homo sapiens
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models.
Year : 2005
Volume : 48
Issue : 23
First Page : 7089
Last Page : 7092
Authors : Carling RW, Madin A, Guiblin A, Russell MG, Moore KW, Mitchinson A, Sohal B, Pike A, Cook SM, Ragan IC, McKernan RM, Quirk K, Ferris P, Marshall G, Thompson SA, Wafford KA, Dawson GR, Atack JR, Harrison T, Castro JL, Street LJ.
Abstract : There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.
|
Displacement of [3H]Ro 15-1788 from human recombinant GABAA alpha-2-beta-3-gamma-2 receptor expressed in L(tk-) cells
|
Homo sapiens
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models.
Year : 2005
Volume : 48
Issue : 23
First Page : 7089
Last Page : 7092
Authors : Carling RW, Madin A, Guiblin A, Russell MG, Moore KW, Mitchinson A, Sohal B, Pike A, Cook SM, Ragan IC, McKernan RM, Quirk K, Ferris P, Marshall G, Thompson SA, Wafford KA, Dawson GR, Atack JR, Harrison T, Castro JL, Street LJ.
Abstract : There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.
|
Displacement of [3H]Ro 15-1788 from human recombinant GABAA alpha-3-beta-3-gamma-2 receptor expressed in L(tk-) cells
|
Homo sapiens
|
380.0
nM
|
|
Journal : J. Med. Chem.
Title : 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models.
Year : 2005
Volume : 48
Issue : 23
First Page : 7089
Last Page : 7092
Authors : Carling RW, Madin A, Guiblin A, Russell MG, Moore KW, Mitchinson A, Sohal B, Pike A, Cook SM, Ragan IC, McKernan RM, Quirk K, Ferris P, Marshall G, Thompson SA, Wafford KA, Dawson GR, Atack JR, Harrison T, Castro JL, Street LJ.
Abstract : There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.
|
Displacement of [3H]Ro15-1788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 receptor expressed in HEK293T cells
|
None
|
61.9
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-2-beta-2-gamma-2 receptor expressed in HEK293T cells
|
None
|
408.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 D56C receptor mutant expressed in HEK293T cells
|
None
|
67.6
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 A79C receptor mutant expressed in HEK293T cells
|
None
|
577.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 T81C receptor mutant expressed in HEK293T cells
|
None
|
108.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 T126C receptor mutant expressed in HEK293T cells
|
None
|
72.7
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 M130C receptor mutant expressed in HEK293T cells
|
None
|
15.5
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 R132C receptor mutant expressed in HEK293T cells
|
None
|
35.8
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 L140C receptor mutant expressed in HEK293T cells
|
None
|
63.1
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 R144C receptor mutant expressed in HEK293T cells
|
None
|
38.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 X161 receptor mutant expressed in HEK293T cells
|
None
|
427.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 R185C receptor mutant expressed in HEK293T cells
|
None
|
67.4
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-1-beta-2-gamma-2 R194C receptor mutant expressed in HEK293T cells
|
None
|
62.6
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro15-1788 from benzodiazepine binding site of GABAA alpha-1 F99C beta2gamma2 receptor mutant expressed in HEK293T cells
|
None
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha1 A160C beta2gamma2 receptor mutant expressed in HEK293T cells
|
None
|
81.4
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro15-1788 from benzodiazepine binding site of GABAA alpha1 T162C beta-2-gamma-2 receptor mutant expressed in HEK293T cells
|
None
|
109.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro15-1788 from benzodiazepine binding site of GABAA alpha-1 G200C beta2gamma2 receptor mutant expressed in HEK293T cells
|
None
|
598.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha1 V202C beta2gamma2 receptor mutant expressed in HEK293T cells
|
None
|
556.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha1 S204C beta2gamma2 receptor mutant expressed in HEK293T cells
|
None
|
433.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha1 S205C beta2gamma2 receptor mutant expressed in HEK293T cells
|
None
|
41.2
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro15-1788 from benzodiazepine binding site of GABAA alpha-1 T206C beta2gamma2 receptor mutant expressed in HEK293T cells
|
None
|
76.4
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro15-1788 from benzodiazepine binding site of GABAA alpha-1 V211C beta2gamma2 receptor mutant expressed in HEK293T cells
|
None
|
67.8
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Displacement of [3H]Ro-151788 from benzodiazepine binding site of GABAA alpha-3-beta-2-gamma-2 receptor expressed in HEK293T cells
|
None
|
975.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
Year : 2008
Volume : 51
Issue : 22
First Page : 7243
Last Page : 7252
Authors : Hanson SM, Morlock EV, Satyshur KA, Czajkowski C.
Abstract : The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
|
Activity at rat wild type GABAA alpha-1V211Cbeta-2-gamma-2 mutant receptor expressed in xenopus oocytes assessed as GABA-elicited response by two electrode voltage clamp method relative to control
|
Rattus norvegicus
|
341.0
nM
|
|
Journal : J. Biol. Chem.
Title : Proximity-accelerated chemical coupling reaction in the benzodiazepine-binding site of gamma-aminobutyric acid type A receptors: superposition of different allosteric modulators.
Year : 2007
Volume : 282
Issue : 36
First Page : 26316
Last Page : 26325
Authors : Tan KR, Gonthier A, Baur R, Ernst M, Goeldner M, Sigel E.
Abstract : Benzodiazepines are widely used drugs. They exert sedative/hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects and act through a specific high affinity binding site on the major inhibitory neurotransmitter receptor, the gamma-aminobutyric acid type A (GABA(A)) receptor. Ligands of the benzodiazepine-binding site are classified into three groups depending on their mode of action: positive and negative allosteric modulators and antagonists. To rationally design ligands of the benzodiazepine site in different isoforms of the GABA(A) receptor, we need to understand the relative positioning and overlap of modulators of different allosteric properties. To solve these questions, we used a proximity-accelerated irreversible chemical coupling reaction. GABA(A) receptor residues thought to reside in the benzodiazepine-binding site were individually mutated to cysteine and combined with a cysteine-reactive benzodiazepine site ligand. Direct apposition of reaction partners is expected to lead to a covalent reaction. We describe here such a reaction of predominantly alpha(1)H101C and also three other mutants (alpha(1)G157C, alpha(1)V202C, and alpha(1)V211C) with an Imid-NCS derivative in which a reactive isothiocyanate group (-NCS) replaces the azide group (-N(3)) in the partial negative allosteric modulator Ro15-4513. Our results show four contact points of imidazobenzodiazepines with the receptor, alpha(1)H101C being shared by classical benzodiazepines. Taken together with previous data, a similar orientation of these ligands within the benzodiazepine-binding pocket may be proposed.
|
Activity at rat GABAA alpha-1H101Cbeta-2-gamma-2 mutant receptor expressed in xenopus oocytes assessed as change in GABA-induced current amplitude at 10 uM after 1 min exposure to GABA by two electrode voltage clamp method
|
Rattus norvegicus
|
220.0
%
|
|
Journal : J. Biol. Chem.
Title : Proximity-accelerated chemical coupling reaction in the benzodiazepine-binding site of gamma-aminobutyric acid type A receptors: superposition of different allosteric modulators.
Year : 2007
Volume : 282
Issue : 36
First Page : 26316
Last Page : 26325
Authors : Tan KR, Gonthier A, Baur R, Ernst M, Goeldner M, Sigel E.
Abstract : Benzodiazepines are widely used drugs. They exert sedative/hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects and act through a specific high affinity binding site on the major inhibitory neurotransmitter receptor, the gamma-aminobutyric acid type A (GABA(A)) receptor. Ligands of the benzodiazepine-binding site are classified into three groups depending on their mode of action: positive and negative allosteric modulators and antagonists. To rationally design ligands of the benzodiazepine site in different isoforms of the GABA(A) receptor, we need to understand the relative positioning and overlap of modulators of different allosteric properties. To solve these questions, we used a proximity-accelerated irreversible chemical coupling reaction. GABA(A) receptor residues thought to reside in the benzodiazepine-binding site were individually mutated to cysteine and combined with a cysteine-reactive benzodiazepine site ligand. Direct apposition of reaction partners is expected to lead to a covalent reaction. We describe here such a reaction of predominantly alpha(1)H101C and also three other mutants (alpha(1)G157C, alpha(1)V202C, and alpha(1)V211C) with an Imid-NCS derivative in which a reactive isothiocyanate group (-NCS) replaces the azide group (-N(3)) in the partial negative allosteric modulator Ro15-4513. Our results show four contact points of imidazobenzodiazepines with the receptor, alpha(1)H101C being shared by classical benzodiazepines. Taken together with previous data, a similar orientation of these ligands within the benzodiazepine-binding pocket may be proposed.
|
Activity at rat GABAA alpha-1H101Cbeta-2-gamma-2 mutant receptor expressed in xenopus oocytes assessed as change in GABA-induced current amplitude at 10 uM after 1 min exposure to GABA by two electrode voltage clamp method
|
Rattus norvegicus
|
96.0
%
|
|
Journal : J. Biol. Chem.
Title : Proximity-accelerated chemical coupling reaction in the benzodiazepine-binding site of gamma-aminobutyric acid type A receptors: superposition of different allosteric modulators.
Year : 2007
Volume : 282
Issue : 36
First Page : 26316
Last Page : 26325
Authors : Tan KR, Gonthier A, Baur R, Ernst M, Goeldner M, Sigel E.
Abstract : Benzodiazepines are widely used drugs. They exert sedative/hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects and act through a specific high affinity binding site on the major inhibitory neurotransmitter receptor, the gamma-aminobutyric acid type A (GABA(A)) receptor. Ligands of the benzodiazepine-binding site are classified into three groups depending on their mode of action: positive and negative allosteric modulators and antagonists. To rationally design ligands of the benzodiazepine site in different isoforms of the GABA(A) receptor, we need to understand the relative positioning and overlap of modulators of different allosteric properties. To solve these questions, we used a proximity-accelerated irreversible chemical coupling reaction. GABA(A) receptor residues thought to reside in the benzodiazepine-binding site were individually mutated to cysteine and combined with a cysteine-reactive benzodiazepine site ligand. Direct apposition of reaction partners is expected to lead to a covalent reaction. We describe here such a reaction of predominantly alpha(1)H101C and also three other mutants (alpha(1)G157C, alpha(1)V202C, and alpha(1)V211C) with an Imid-NCS derivative in which a reactive isothiocyanate group (-NCS) replaces the azide group (-N(3)) in the partial negative allosteric modulator Ro15-4513. Our results show four contact points of imidazobenzodiazepines with the receptor, alpha(1)H101C being shared by classical benzodiazepines. Taken together with previous data, a similar orientation of these ligands within the benzodiazepine-binding pocket may be proposed.
|
Activity at rat wild type GABAA alpha-1-beta-2-gamma-2 receptor expressed in xenopus oocytes assessed as GABA-elicited response by two electrode voltage clamp method relative to control
|
Rattus norvegicus
|
191.0
nM
|
|
Journal : J. Biol. Chem.
Title : Proximity-accelerated chemical coupling reaction in the benzodiazepine-binding site of gamma-aminobutyric acid type A receptors: superposition of different allosteric modulators.
Year : 2007
Volume : 282
Issue : 36
First Page : 26316
Last Page : 26325
Authors : Tan KR, Gonthier A, Baur R, Ernst M, Goeldner M, Sigel E.
Abstract : Benzodiazepines are widely used drugs. They exert sedative/hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects and act through a specific high affinity binding site on the major inhibitory neurotransmitter receptor, the gamma-aminobutyric acid type A (GABA(A)) receptor. Ligands of the benzodiazepine-binding site are classified into three groups depending on their mode of action: positive and negative allosteric modulators and antagonists. To rationally design ligands of the benzodiazepine site in different isoforms of the GABA(A) receptor, we need to understand the relative positioning and overlap of modulators of different allosteric properties. To solve these questions, we used a proximity-accelerated irreversible chemical coupling reaction. GABA(A) receptor residues thought to reside in the benzodiazepine-binding site were individually mutated to cysteine and combined with a cysteine-reactive benzodiazepine site ligand. Direct apposition of reaction partners is expected to lead to a covalent reaction. We describe here such a reaction of predominantly alpha(1)H101C and also three other mutants (alpha(1)G157C, alpha(1)V202C, and alpha(1)V211C) with an Imid-NCS derivative in which a reactive isothiocyanate group (-NCS) replaces the azide group (-N(3)) in the partial negative allosteric modulator Ro15-4513. Our results show four contact points of imidazobenzodiazepines with the receptor, alpha(1)H101C being shared by classical benzodiazepines. Taken together with previous data, a similar orientation of these ligands within the benzodiazepine-binding pocket may be proposed.
|
Displacement of [3H]flumazenil from Benzodiazepine receptor in bovine cerebral cortex membrane
|
Bos taurus
|
51.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of anxiolytic/nonsedative agents among indol-3-ylglyoxylamides acting as functionally selective agonists at the gamma-aminobutyric acid-A (GABAA) alpha2 benzodiazepine receptor.
Year : 2009
Volume : 52
Issue : 12
First Page : 3723
Last Page : 3734
Authors : Taliani S, Cosimelli B, Da Settimo F, Marini AM, La Motta C, Simorini F, Salerno S, Novellino E, Greco G, Cosconati S, Marinelli L, Salvetti F, L'Abbate G, Trasciatti S, Montali M, Costa B, Martini C.
Abstract : Anxioselective agents may be identified among compounds binding selectively to the alpha(2)beta(x)gamma(2) subtype of the gamma-aminobutyric acid-A (GABA(A))/central benzodiazepine receptor (BzR) complex and behaving as agonists or among compounds binding with comparable potency to various BzR subtypes but eliciting agonism only at the alpha(2)beta(x)gamma(2) receptor. Because of subtle steric differences among BzR subtypes, the latter approach has proved much more successful. A biological screening within the class of indol-3-ylglyoxylamides 1-3 allowed us to identify compounds 1c and 2b as potential anxiolytic/nonsedative agents showing alpha(2) selective efficacy in vitro and anxioselective effects in vivo. According to molecular modeling studies, and consistently with SARs accumulated in the past decade, 5-NO(2)- and 5-H-indole derivatives would preferentially bind to BzR by placing the indole ring in the L(Di) and the L(2) receptor binding sites, respectively.
|
Displacement of [3H]flumazenil from rat GABA-A alpha-1-beta-2-gamma-2 receptor expressed in HEK293 cells
|
Rattus norvegicus
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of anxiolytic/nonsedative agents among indol-3-ylglyoxylamides acting as functionally selective agonists at the gamma-aminobutyric acid-A (GABAA) alpha2 benzodiazepine receptor.
Year : 2009
Volume : 52
Issue : 12
First Page : 3723
Last Page : 3734
Authors : Taliani S, Cosimelli B, Da Settimo F, Marini AM, La Motta C, Simorini F, Salerno S, Novellino E, Greco G, Cosconati S, Marinelli L, Salvetti F, L'Abbate G, Trasciatti S, Montali M, Costa B, Martini C.
Abstract : Anxioselective agents may be identified among compounds binding selectively to the alpha(2)beta(x)gamma(2) subtype of the gamma-aminobutyric acid-A (GABA(A))/central benzodiazepine receptor (BzR) complex and behaving as agonists or among compounds binding with comparable potency to various BzR subtypes but eliciting agonism only at the alpha(2)beta(x)gamma(2) receptor. Because of subtle steric differences among BzR subtypes, the latter approach has proved much more successful. A biological screening within the class of indol-3-ylglyoxylamides 1-3 allowed us to identify compounds 1c and 2b as potential anxiolytic/nonsedative agents showing alpha(2) selective efficacy in vitro and anxioselective effects in vivo. According to molecular modeling studies, and consistently with SARs accumulated in the past decade, 5-NO(2)- and 5-H-indole derivatives would preferentially bind to BzR by placing the indole ring in the L(Di) and the L(2) receptor binding sites, respectively.
|
Displacement of [3H]flumazenil from rat GABA-A alpha-2-beta-2-gamma-2 receptor expressed in HEK293 cells
|
Rattus norvegicus
|
765.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of anxiolytic/nonsedative agents among indol-3-ylglyoxylamides acting as functionally selective agonists at the gamma-aminobutyric acid-A (GABAA) alpha2 benzodiazepine receptor.
Year : 2009
Volume : 52
Issue : 12
First Page : 3723
Last Page : 3734
Authors : Taliani S, Cosimelli B, Da Settimo F, Marini AM, La Motta C, Simorini F, Salerno S, Novellino E, Greco G, Cosconati S, Marinelli L, Salvetti F, L'Abbate G, Trasciatti S, Montali M, Costa B, Martini C.
Abstract : Anxioselective agents may be identified among compounds binding selectively to the alpha(2)beta(x)gamma(2) subtype of the gamma-aminobutyric acid-A (GABA(A))/central benzodiazepine receptor (BzR) complex and behaving as agonists or among compounds binding with comparable potency to various BzR subtypes but eliciting agonism only at the alpha(2)beta(x)gamma(2) receptor. Because of subtle steric differences among BzR subtypes, the latter approach has proved much more successful. A biological screening within the class of indol-3-ylglyoxylamides 1-3 allowed us to identify compounds 1c and 2b as potential anxiolytic/nonsedative agents showing alpha(2) selective efficacy in vitro and anxioselective effects in vivo. According to molecular modeling studies, and consistently with SARs accumulated in the past decade, 5-NO(2)- and 5-H-indole derivatives would preferentially bind to BzR by placing the indole ring in the L(Di) and the L(2) receptor binding sites, respectively.
|
Displacement of [3H]flumazenil from rat GABA-A alpha-5-beta-3-gamma-2 receptor expressed in HEK293 cells
|
Rattus norvegicus
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of anxiolytic/nonsedative agents among indol-3-ylglyoxylamides acting as functionally selective agonists at the gamma-aminobutyric acid-A (GABAA) alpha2 benzodiazepine receptor.
Year : 2009
Volume : 52
Issue : 12
First Page : 3723
Last Page : 3734
Authors : Taliani S, Cosimelli B, Da Settimo F, Marini AM, La Motta C, Simorini F, Salerno S, Novellino E, Greco G, Cosconati S, Marinelli L, Salvetti F, L'Abbate G, Trasciatti S, Montali M, Costa B, Martini C.
Abstract : Anxioselective agents may be identified among compounds binding selectively to the alpha(2)beta(x)gamma(2) subtype of the gamma-aminobutyric acid-A (GABA(A))/central benzodiazepine receptor (BzR) complex and behaving as agonists or among compounds binding with comparable potency to various BzR subtypes but eliciting agonism only at the alpha(2)beta(x)gamma(2) receptor. Because of subtle steric differences among BzR subtypes, the latter approach has proved much more successful. A biological screening within the class of indol-3-ylglyoxylamides 1-3 allowed us to identify compounds 1c and 2b as potential anxiolytic/nonsedative agents showing alpha(2) selective efficacy in vitro and anxioselective effects in vivo. According to molecular modeling studies, and consistently with SARs accumulated in the past decade, 5-NO(2)- and 5-H-indole derivatives would preferentially bind to BzR by placing the indole ring in the L(Di) and the L(2) receptor binding sites, respectively.
|
Displacement of [3H]flunitrazepam from human recombinant GABAA alpha-1-beta-3-gamma-2 receptor expressed in HEK cells by liquid scintillation counting
|
Homo sapiens
|
26.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse.
Year : 2010
Volume : 18
Issue : 21
First Page : 7548
Last Page : 7564
Authors : Yin W, Majumder S, Clayton T, Petrou S, VanLinn ML, Namjoshi OA, Ma C, Cromer BA, Roth BL, Platt DM, Cook JM.
Abstract : A series of 3,6-disubstituted β-carbolines was synthesized and evaluated for their in vitro affinities at α(x)β(3)γ(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of α(1) subtype selective ligands to treat alcohol abuse. Analogues of β-carboline-3-carboxylate-t-butyl ester (βCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted β-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-βCCt (5). The bivalent ligands of βCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position-6 of the β-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L(Di) region) of GABA(A)/Bz receptors (see 32 and 33). Moreover, substituents located at position-3 of the β-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L(1), while N(2) presumably underwent a hydrogen bonding interaction with H(1). Three novel β-carboline ligands (βCCt, 3PBC and WYS8), which preferentially bound to α1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these β-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) α(1) selective ligand was the 6-substituted acetylenyl βCCt (WYS8, 7). Earlier both βCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration.(1-3) Moreover, these two β-carbolines were orally active, and in addition, were anxiolytic in P rats but were only weakly anxiolytic in rodents. These data prompted the synthesis of the β-carbolines presented here.
|
Displacement of [3H]flunitrazepam from human recombinant GABAA alpha-2-beta-3-gamma-2 receptor expressed in HEK cells by liquid scintillation counting
|
Homo sapiens
|
156.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse.
Year : 2010
Volume : 18
Issue : 21
First Page : 7548
Last Page : 7564
Authors : Yin W, Majumder S, Clayton T, Petrou S, VanLinn ML, Namjoshi OA, Ma C, Cromer BA, Roth BL, Platt DM, Cook JM.
Abstract : A series of 3,6-disubstituted β-carbolines was synthesized and evaluated for their in vitro affinities at α(x)β(3)γ(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of α(1) subtype selective ligands to treat alcohol abuse. Analogues of β-carboline-3-carboxylate-t-butyl ester (βCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted β-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-βCCt (5). The bivalent ligands of βCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position-6 of the β-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L(Di) region) of GABA(A)/Bz receptors (see 32 and 33). Moreover, substituents located at position-3 of the β-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L(1), while N(2) presumably underwent a hydrogen bonding interaction with H(1). Three novel β-carboline ligands (βCCt, 3PBC and WYS8), which preferentially bound to α1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these β-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) α(1) selective ligand was the 6-substituted acetylenyl βCCt (WYS8, 7). Earlier both βCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration.(1-3) Moreover, these two β-carbolines were orally active, and in addition, were anxiolytic in P rats but were only weakly anxiolytic in rodents. These data prompted the synthesis of the β-carbolines presented here.
|
Displacement of [3H]flunitrazepam from human recombinant GABAA alpha-3-beta-3-gamma-2 receptor expressed in HEK cells by liquid scintillation counting
|
Homo sapiens
|
383.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse.
Year : 2010
Volume : 18
Issue : 21
First Page : 7548
Last Page : 7564
Authors : Yin W, Majumder S, Clayton T, Petrou S, VanLinn ML, Namjoshi OA, Ma C, Cromer BA, Roth BL, Platt DM, Cook JM.
Abstract : A series of 3,6-disubstituted β-carbolines was synthesized and evaluated for their in vitro affinities at α(x)β(3)γ(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of α(1) subtype selective ligands to treat alcohol abuse. Analogues of β-carboline-3-carboxylate-t-butyl ester (βCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted β-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-βCCt (5). The bivalent ligands of βCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position-6 of the β-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L(Di) region) of GABA(A)/Bz receptors (see 32 and 33). Moreover, substituents located at position-3 of the β-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L(1), while N(2) presumably underwent a hydrogen bonding interaction with H(1). Three novel β-carboline ligands (βCCt, 3PBC and WYS8), which preferentially bound to α1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these β-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) α(1) selective ligand was the 6-substituted acetylenyl βCCt (WYS8, 7). Earlier both βCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration.(1-3) Moreover, these two β-carbolines were orally active, and in addition, were anxiolytic in P rats but were only weakly anxiolytic in rodents. These data prompted the synthesis of the β-carbolines presented here.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
177.44
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
78.05
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Displacement of [3H]-flunitrazepam from rat brain GABA-A receptor benzodiazepine site after 20 mins by liquid scintillation counting
|
Rattus norvegicus
|
44.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of fluorinated imidazo[1,2-a]pyridine derivatives with potential antipsychotic activity.
Year : 2016
Volume : 124
First Page : 456
Last Page : 467
Authors : Marcinkowska M, Kołaczkowski M, Kamiński K, Bucki A, Pawłowski M, Siwek A, Karcz T, Mordyl B, Starowicz G, Kubowicz P, Pękala E, Wesołowska A, Samochowiec J, Mierzejewski P, Bienkowski P.
Abstract : Based on our recent finding that α1 selective GABA-A receptor potentiator-zolpidem-(a hypnotic drug) exerts antipsychotic-like effects in rats, we developed a series of fluorinated imidazo[1,2-a]pyridine derivatives as potential novel antipsychotic agents. The selected compounds displayed high affinity and positive allosteric modulator properties at the GABA-A receptor, enhanced metabolic stability and lack of hepatotoxicity. The most promising compound 2-(2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylethanamide (26) showed antipsychotic-like activity in amphetamine-induced hyperlocomotion test in rats (MED = 1 mg/kg) and was characterized by a longer duration of antipsychotic-like activity as compared to zolpidem. These results are an encouraging example of a compound with non-dopaminergic mechanism of action displaying antipsychotic activity and are a point of entry for the future studies in this field.
|
Positive allosteric modulation of human recombinant GABA-A receptor alpha1beta2gamma2 expressed in HEK293 cells assessed as potentiation of of GABA induced chloride currents treated every 60 secs measured for 7 secs by electrophysiological method
|
Homo sapiens
|
240.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of fluorinated imidazo[1,2-a]pyridine derivatives with potential antipsychotic activity.
Year : 2016
Volume : 124
First Page : 456
Last Page : 467
Authors : Marcinkowska M, Kołaczkowski M, Kamiński K, Bucki A, Pawłowski M, Siwek A, Karcz T, Mordyl B, Starowicz G, Kubowicz P, Pękala E, Wesołowska A, Samochowiec J, Mierzejewski P, Bienkowski P.
Abstract : Based on our recent finding that α1 selective GABA-A receptor potentiator-zolpidem-(a hypnotic drug) exerts antipsychotic-like effects in rats, we developed a series of fluorinated imidazo[1,2-a]pyridine derivatives as potential novel antipsychotic agents. The selected compounds displayed high affinity and positive allosteric modulator properties at the GABA-A receptor, enhanced metabolic stability and lack of hepatotoxicity. The most promising compound 2-(2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylethanamide (26) showed antipsychotic-like activity in amphetamine-induced hyperlocomotion test in rats (MED = 1 mg/kg) and was characterized by a longer duration of antipsychotic-like activity as compared to zolpidem. These results are an encouraging example of a compound with non-dopaminergic mechanism of action displaying antipsychotic activity and are a point of entry for the future studies in this field.
|
Displacement of [3H]RO15-1788 from recombinant rat GABAalpha1 receptor expressed in HEK293 cells after 1 hr
|
Rattus norvegicus
|
26.7
nM
|
|
Journal : Eur J Med Chem
Title : An insight on synthetic and medicinal aspects of pyrazolo[1,5-a]pyrimidine scaffold.
Year : 2017
Volume : 126
First Page : 298
Last Page : 352
Authors : Cherukupalli S, Karpoormath R, Chandrasekaran B, Hampannavar GA, Thapliyal N, Palakollu VN.
Abstract : Pyrazolo[1,5-a]pyrimidine scaffold is one of the privileged hetrocycles in drug discovery. Its application as a buliding block for developing drug-like candidates has displayed broad range of medicinal properties such as anticancer, CNS agents, anti-infectious, anti-inflammatory, CRF1 antagonists and radio diagnostics. The structure-activity relationship (SAR) studies have acquired greater attention amid medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is plenty of room for the medicinal chemists to further exploit this privileged scaffold in developing potential drug candidates. The present review briefly outlines relevant synthetic strategies employed for pyrazolo[1,5-a]pyrimidine derivatives. It also extensively reveals significant biological properties along with SAR studies. To the best of our understanding current review is the first attempt made towards the compilation of significant advances made on pyrazolo[1,5-a]pyrimidines reported since 1980s.
|
Displacement of [3H]RO15-1788 from recombinant rat GABAalpha2 receptor expressed in HEK293 cells after 1 hr
|
Rattus norvegicus
|
156.0
nM
|
|
Journal : Eur J Med Chem
Title : An insight on synthetic and medicinal aspects of pyrazolo[1,5-a]pyrimidine scaffold.
Year : 2017
Volume : 126
First Page : 298
Last Page : 352
Authors : Cherukupalli S, Karpoormath R, Chandrasekaran B, Hampannavar GA, Thapliyal N, Palakollu VN.
Abstract : Pyrazolo[1,5-a]pyrimidine scaffold is one of the privileged hetrocycles in drug discovery. Its application as a buliding block for developing drug-like candidates has displayed broad range of medicinal properties such as anticancer, CNS agents, anti-infectious, anti-inflammatory, CRF1 antagonists and radio diagnostics. The structure-activity relationship (SAR) studies have acquired greater attention amid medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is plenty of room for the medicinal chemists to further exploit this privileged scaffold in developing potential drug candidates. The present review briefly outlines relevant synthetic strategies employed for pyrazolo[1,5-a]pyrimidine derivatives. It also extensively reveals significant biological properties along with SAR studies. To the best of our understanding current review is the first attempt made towards the compilation of significant advances made on pyrazolo[1,5-a]pyrimidines reported since 1980s.
|
Displacement of [3H]RO15-1788 from recombinant rat GABAalpha3 receptor expressed in HEK293 cells after 1 hr
|
Rattus norvegicus
|
383.0
nM
|
|
Journal : Eur J Med Chem
Title : An insight on synthetic and medicinal aspects of pyrazolo[1,5-a]pyrimidine scaffold.
Year : 2017
Volume : 126
First Page : 298
Last Page : 352
Authors : Cherukupalli S, Karpoormath R, Chandrasekaran B, Hampannavar GA, Thapliyal N, Palakollu VN.
Abstract : Pyrazolo[1,5-a]pyrimidine scaffold is one of the privileged hetrocycles in drug discovery. Its application as a buliding block for developing drug-like candidates has displayed broad range of medicinal properties such as anticancer, CNS agents, anti-infectious, anti-inflammatory, CRF1 antagonists and radio diagnostics. The structure-activity relationship (SAR) studies have acquired greater attention amid medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is plenty of room for the medicinal chemists to further exploit this privileged scaffold in developing potential drug candidates. The present review briefly outlines relevant synthetic strategies employed for pyrazolo[1,5-a]pyrimidine derivatives. It also extensively reveals significant biological properties along with SAR studies. To the best of our understanding current review is the first attempt made towards the compilation of significant advances made on pyrazolo[1,5-a]pyrimidines reported since 1980s.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
0.52
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of GABAA receptor alpha1 (unknown origin)
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Imidazopyridine-based selective and multifunctional ligands of biological targets associated with psychiatric and neurodegenerative diseases.
Year : 2019
Volume : 181
First Page : 111569
Last Page : 111569
Authors : Vanda D, Zajdel P, Soural M.
Abstract : This article provides an overview of compounds based on imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine scaffolds, which act as potent ligands of diverse molecular targets localized in the central nervous system. A literature survey revealed that various imidazopyridines can be powerful modulators of several diseases associated with CNS dysfunction including Alzheimer's disease, Parkinson's disease, schizophrenia, depression or sleeping disorders. A description of target enzymes (e.g., β-secretase, γ-secretase, fatty acid amide hydrolase - FAAH, leucine-rich repeat kinase 2 - LRRK2) and selected receptors (e.g., GABA-A, histamine H<sub>3</sub>, serotonin 5-HT<sub>3</sub>, 5-HT<sub>4</sub>, 5-HT<sub>6</sub>, dopamine D<sub>4</sub>, adenosine A<sub>2A</sub>, orexin), modes of action of imidazopyridine-based ligands and their therapeutic importance is discussed.
|
Inhibition of GABAA receptor alpha3 (unknown origin)
|
Homo sapiens
|
400.0
nM
|
|
Journal : Eur J Med Chem
Title : Imidazopyridine-based selective and multifunctional ligands of biological targets associated with psychiatric and neurodegenerative diseases.
Year : 2019
Volume : 181
First Page : 111569
Last Page : 111569
Authors : Vanda D, Zajdel P, Soural M.
Abstract : This article provides an overview of compounds based on imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine scaffolds, which act as potent ligands of diverse molecular targets localized in the central nervous system. A literature survey revealed that various imidazopyridines can be powerful modulators of several diseases associated with CNS dysfunction including Alzheimer's disease, Parkinson's disease, schizophrenia, depression or sleeping disorders. A description of target enzymes (e.g., β-secretase, γ-secretase, fatty acid amide hydrolase - FAAH, leucine-rich repeat kinase 2 - LRRK2) and selected receptors (e.g., GABA-A, histamine H<sub>3</sub>, serotonin 5-HT<sub>3</sub>, 5-HT<sub>4</sub>, 5-HT<sub>6</sub>, dopamine D<sub>4</sub>, adenosine A<sub>2A</sub>, orexin), modes of action of imidazopyridine-based ligands and their therapeutic importance is discussed.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
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Severe acute respiratory syndrome coronavirus 2
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4.533
%
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Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
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Chlorocebus sabaeus
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-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
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Chlorocebus sabaeus
|
-0.09
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
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Positive allosteric modulator activity at rat alpha1beta2gamma2L GABA-A receptor expressed in Xenopus laevis oocytes in presence of EC2-5 GABA by two-electrode voltage clamp assay
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Rattus norvegicus
|
340.0
nM
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Journal : ACS Med Chem Lett
Title : Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABA Receptor.
Year : 2020
Volume : 11
Issue : 11
First Page : 2204
Last Page : 2211
Authors : Blom AEM,Su JY,Repka LM,Reisman SE,Dougherty DA
Abstract : γ-Aminobutyric acid type A (GABA) receptors are key mediators of central inhibitory neurotransmission and have been implicated in several disorders of the central nervous system. Some positive allosteric modulators (PAMs) of this receptor provide great therapeutic benefits to patients. However, adverse effects remain a challenge. Selective targeting of GABA receptors could mitigate this problem. Here, we describe the synthesis and functional evaluation of a novel series of pyrroloindolines that display significant modulation of the GABA receptor, acting as PAMs. We found that halogen incorporation at the C5 position greatly increased the PAM potency relative to the parent ligand, while substitutions at other positions generally decreased potency. Mutagenesis studies suggest that the binding site lies at the top of the transmembrane domain.
