|
In vitro binding affinity towards (alpha-4)2(beta-2)3 neuronal nicotinic acetylcholine receptor in P2 membrane fractions of rat forebrain
|
None
|
0.123
nM
|
|
Journal : J. Med. Chem.
Title : 3D QSAR analyses-guided rational design of novel ligands for the (alpha4)2(beta2)3 nicotinic acetylcholine receptor.
Year : 2003
Volume : 46
Issue : 11
First Page : 2031
Last Page : 2048
Authors : Gohlke H, Schwarz S, Gündisch D, Tilotta MC, Weber A, Wegge T, Seitz G.
Abstract : Three-dimensional quantitative structure-activity relationship methods, the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA), were applied using a training set of 45 ligands of the (alpha4)2(beta2)3 nicotinic acetylcholine receptor (nAChR). All compounds are related to (-)-epibatidine, (-)-cytisine, (+)-anatoxin-a, and (-)-ferruginine, and additionally, novel diazabicyclo[4.2.1]nonane- and quinuclidin-2-ene-based structures were included. Their biological data have been determined by utilizing the same experimental protocol. Statistically reliable models of good predictive power (CoMFA r2 = 0.928, q2 = 0.692, no. of components = 3; CoMSIA r2 = 0.899, q2 = 0.701, no. of components = 3) were achieved. The results obtained were graphically interpreted in terms of field contribution maps. Hence, physicochemical determinants of binding, such as steric and electrostatic and, for the first time, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor properties, were mapped back onto the molecular structures of a set of nAChR modulators. In particular, changes in the binding affinity of the modulators as a result of modifications in the aromatic ring systems could be rationalized by the steric, electrostatic, hydrophobic, and hydrogen bond acceptor properties. These results were used to guide the rational design of new nAChR ligands such as 48-52 and 54, which were subsequently synthesized for the first time and tested. Key steps of our synthetic approaches were successfully applied Stille and Suzuki cross-coupling reactions. Predictive r2 values of 0.614 and 0.660 for CoMFA and CoMSIA, respectively, obtained for 22 in part previously unknown ligands for the (alpha4)2(beta2)3 subtype, demonstrate the high quality of the 3D QSAR models.
|
Binding affinity towards rat forebrain nicotinic acetylcholine receptor using [3H]EB as radioligand
|
Rattus norvegicus
|
2.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Binding affinity towards rat nicotinic acetylcholine receptor alpha2-beta2 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
1.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Binding affinity towards rat Nicotinic acetylcholine receptor alpha3-beta2 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Binding affinity towards rat Nicotinic acetylcholine receptor alpha3-beta4 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
210.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
In vitro binding affinity by inhibiting [3H]dopamine release in rat brain tissue at Nicotinic acetylcholine receptor alpha4-beta2
|
Rattus norvegicus
|
8.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation at nicotinic acetylcholine receptors of N-arylalkyl- and N-aryl-7-azabicyclo[2.2.1]heptanes.
Year : 2002
Volume : 45
Issue : 14
First Page : 3041
Last Page : 3047
Authors : Cheng J, Zhang C, Stevens ED, Izenwasser S, Wade D, Chen S, Paul D, Trudell ML.
Abstract : A new series of N-arylalkyl-substituted 7-azabicyclo[2.2.1]heptanes and N-aryl-substituted 7-azabicyclo[2.2.1]heptanes were synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors. The in vitro binding affinities (K(i)) of the 7-azabicyclo[2.2.1]heptane derivatives were measured by inhibition of [(3)H]cytisine binding to rat brain tissue. The most potent ligand of the series was found to be N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]heptane (5b, K(i) = 98 nM). The chloro analogue (5a, K(i) = 245 nM) 5a and epibatidine (1) produced dose-dependent analgesia in both hotplate and tail-flick tests when administered subcutaneously. However, when compounds 1 and 5a,b were administered intrathecally, all produced analgesia in the tail-flick test but only 5a produced analgesia in the hotplate test.
|
Binding affinity towards rat Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
1.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
In vitro binding affinity towards Nicotinic acetylcholine receptor alpha4-beta2 using [3H]cytisine in rat brain
|
Rattus norvegicus
|
2.78
nM
|
|
Journal : J. Med. Chem.
Title : 2-(2-Piperidyl)- and 2-(2-pyrrolidyl)chromans as nicotine agonists: synthesis and preliminary pharmacological characterization.
Year : 2001
Volume : 44
Issue : 26
First Page : 4704
Last Page : 4715
Authors : Efange SM, Tu Z, von Hohenberg K, Francesconi L, Howell RC, Rampersad MV, Todaro LJ, Papke RL, Kung MP.
Abstract : As part of an effort to develop a new class of subtype selective nicotine agonists, we have synthesized and tested a group of 12 hydroxylated 2-(2-piperidyl)- and 2-(2-pyrrolidyl)chromans. In rat brain membranes, all 12 compounds displayed poor affinity for [(125)I]-alpha-bunagarotoxin binding sites. In contrast, three compounds, 17c, 24, and 26, displayed moderate to high affinity for [(3)H]cytisine binding sites, while three (17b, 18b,c) and six (17a,d,e and 18a,d,e) compounds showed weak and poor affinity, respectively, for these same sites. In subsequent studies, compounds 17a and 17c were found to stimulate the efflux of (86)Rb(+) from rat cortical synaptosomes, an indication of agonist activity. Further, both 17c and 26 displayed high intrinsic activity in stimulating the release of [(3)H]dopamine from striatal synaptosomes; however, only 17c was effective at stimulating the release of [(3)H]acetylcholine from cortical synaptosomes, suggesting differential selectivity. In cloned human nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, both 17c and 26 activated alpha7 and alpha3beta2 receptor subtypes in a dose-dependent manner, but 26 was clearly the more potent agonist. Last, neither compound displayed dose-dependent activation of alpha4beta2 nAChRs. We conclude that 2-(2-azacyclic)chromans appear to be a promising new class of nicotine agonists.
|
in vitro binding affinity by inhibiting [3H]cytisine binding in rat brain tissue at Nicotinic acetylcholine receptor alpha4-beta2
|
Rattus norvegicus
|
4.2
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation at nicotinic acetylcholine receptors of N-arylalkyl- and N-aryl-7-azabicyclo[2.2.1]heptanes.
Year : 2002
Volume : 45
Issue : 14
First Page : 3041
Last Page : 3047
Authors : Cheng J, Zhang C, Stevens ED, Izenwasser S, Wade D, Chen S, Paul D, Trudell ML.
Abstract : A new series of N-arylalkyl-substituted 7-azabicyclo[2.2.1]heptanes and N-aryl-substituted 7-azabicyclo[2.2.1]heptanes were synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors. The in vitro binding affinities (K(i)) of the 7-azabicyclo[2.2.1]heptane derivatives were measured by inhibition of [(3)H]cytisine binding to rat brain tissue. The most potent ligand of the series was found to be N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]heptane (5b, K(i) = 98 nM). The chloro analogue (5a, K(i) = 245 nM) 5a and epibatidine (1) produced dose-dependent analgesia in both hotplate and tail-flick tests when administered subcutaneously. However, when compounds 1 and 5a,b were administered intrathecally, all produced analgesia in the tail-flick test but only 5a produced analgesia in the hotplate test.
|
Binding affinity towards rat Nicotinic acetylcholine receptor alpha4-beta4 expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
2.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
In vitro binding affinity towards Nicotinic acetylcholine receptor alpha7 using [125I]-alpha-Bungarotoxin in rat brain
|
Rattus norvegicus
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : 2-(2-Piperidyl)- and 2-(2-pyrrolidyl)chromans as nicotine agonists: synthesis and preliminary pharmacological characterization.
Year : 2001
Volume : 44
Issue : 26
First Page : 4704
Last Page : 4715
Authors : Efange SM, Tu Z, von Hohenberg K, Francesconi L, Howell RC, Rampersad MV, Todaro LJ, Papke RL, Kung MP.
Abstract : As part of an effort to develop a new class of subtype selective nicotine agonists, we have synthesized and tested a group of 12 hydroxylated 2-(2-piperidyl)- and 2-(2-pyrrolidyl)chromans. In rat brain membranes, all 12 compounds displayed poor affinity for [(125)I]-alpha-bunagarotoxin binding sites. In contrast, three compounds, 17c, 24, and 26, displayed moderate to high affinity for [(3)H]cytisine binding sites, while three (17b, 18b,c) and six (17a,d,e and 18a,d,e) compounds showed weak and poor affinity, respectively, for these same sites. In subsequent studies, compounds 17a and 17c were found to stimulate the efflux of (86)Rb(+) from rat cortical synaptosomes, an indication of agonist activity. Further, both 17c and 26 displayed high intrinsic activity in stimulating the release of [(3)H]dopamine from striatal synaptosomes; however, only 17c was effective at stimulating the release of [(3)H]acetylcholine from cortical synaptosomes, suggesting differential selectivity. In cloned human nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, both 17c and 26 activated alpha7 and alpha3beta2 receptor subtypes in a dose-dependent manner, but 26 was clearly the more potent agonist. Last, neither compound displayed dose-dependent activation of alpha4beta2 nAChRs. We conclude that 2-(2-azacyclic)chromans appear to be a promising new class of nicotine agonists.
|
Compound was evaluated for functional potencies and efficacies at rat nAChR subtype DA release
|
Rattus norvegicus
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Neuronal nicotinic acetylcholine receptors as targets for drug discovery.
Year : 1997
Volume : 40
Issue : 26
First Page : 4169
Last Page : 4194
Authors : Holladay MW, Dart MJ, Lynch JK.
|
Binding affinity towards rat alpha2-beta4 nACh receptor expressed in HEK293 cells using [3H]EB as radioligand
|
Rattus norvegicus
|
5.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells.
Year : 2004
Volume : 14
Issue : 8
First Page : 1845
Last Page : 1848
Authors : Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ.
Abstract : The binding affinities of agonists at heteromeric nicotinic receptors composed of rat alpha2, alpha3 and alpha4 subunits in combination with beta2 or beta4 subunits were examined in stably transfected HEK 293 cells. In most cases, the affinities of agonists were higher at receptors composed of an alpha subunit in combination with the beta2 subunit than the beta4 subunit, and in some cases this difference was quite large (>250 times), suggesting the possibility of developing subtype-selective ligands and therapeutically useful drugs.
|
Inhibition of [3H]-nicotine binding to nicotinic acetylcholine receptor alpha4-beta2 in rat cortex
|
Rattus norvegicus
|
0.17
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In pursuit of alpha4beta2 nicotinic receptor partial agonists for smoking cessation: carbon analogs of (-)-cytisine.
Year : 2005
Volume : 15
Issue : 12
First Page : 2974
Last Page : 2979
Authors : Coe JW, Vetelino MG, Bashore CG, Wirtz MC, Brooks PR, Arnold EP, Lebel LA, Fox CB, Sands SB, Davis TI, Schulz DW, Rollema H, Tingley FD, O'Neill BT.
Abstract : The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
|
Inhibition of [3H]nicotine binding to nicotinic acetylcholine receptor alpha4-beta2 of rat cortex
|
Rattus norvegicus
|
0.17
nM
|
|
Journal : J. Med. Chem.
Title : Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.
Year : 2005
Volume : 48
Issue : 10
First Page : 3474
Last Page : 3477
Authors : Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD, O'Neill BT.
Abstract : Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
|
Inhibition of [3H]epibatidine binding to nicotinic acetylcholine receptor alpha3-beta4 of human IMR32 cells
|
Homo sapiens
|
840.0
nM
|
|
Journal : J. Med. Chem.
Title : Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.
Year : 2005
Volume : 48
Issue : 10
First Page : 3474
Last Page : 3477
Authors : Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD, O'Neill BT.
Abstract : Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
|
Binding affinity against nicotinic acetylcholine receptor alpha4-beta2 in human HEK293 cells using [3H]- nicotine as radioligand
|
Homo sapiens
|
0.23
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In pursuit of alpha4beta2 nicotinic receptor partial agonists for smoking cessation: carbon analogs of (-)-cytisine.
Year : 2005
Volume : 15
Issue : 12
First Page : 2974
Last Page : 2979
Authors : Coe JW, Vetelino MG, Bashore CG, Wirtz MC, Brooks PR, Arnold EP, Lebel LA, Fox CB, Sands SB, Davis TI, Schulz DW, Rollema H, Tingley FD, O'Neill BT.
Abstract : The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
|
Inhibition of [3H]epibatidine binding to nicotinic acetylcholine receptor alpha3-beta4 of IMR32 cells
|
Homo sapiens
|
840.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In pursuit of alpha4beta2 nicotinic receptor partial agonists for smoking cessation: carbon analogs of (-)-cytisine.
Year : 2005
Volume : 15
Issue : 12
First Page : 2974
Last Page : 2979
Authors : Coe JW, Vetelino MG, Bashore CG, Wirtz MC, Brooks PR, Arnold EP, Lebel LA, Fox CB, Sands SB, Davis TI, Schulz DW, Rollema H, Tingley FD, O'Neill BT.
Abstract : The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
|
Inhibition of [3H]alpha-bungarotoxin binding to nicotinic acetylcholine receptor alpha-1-beta-1-delta-gamma of electroplax
|
pisces
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In pursuit of alpha4beta2 nicotinic receptor partial agonists for smoking cessation: carbon analogs of (-)-cytisine.
Year : 2005
Volume : 15
Issue : 12
First Page : 2974
Last Page : 2979
Authors : Coe JW, Vetelino MG, Bashore CG, Wirtz MC, Brooks PR, Arnold EP, Lebel LA, Fox CB, Sands SB, Davis TI, Schulz DW, Rollema H, Tingley FD, O'Neill BT.
Abstract : The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
|
Inhibition of [125I]alpha-bungarotoxin binding to nicotinic acetylcholine receptor alpha1 beta gamma delta of electroplax
|
None
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.
Year : 2005
Volume : 48
Issue : 10
First Page : 3474
Last Page : 3477
Authors : Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD, O'Neill BT.
Abstract : Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
|
Effective concentration against Nicotinic acetylcholine receptor alpha4-beta4 expressed in xenopus oocytes
|
None
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations.
Year : 2005
Volume : 48
Issue : 15
First Page : 4705
Last Page : 4745
Authors : Jensen AA, Frølund B, Liljefors T, Krogsgaard-Larsen P.
|
Percent antagonist activity against 10 uM nicotine at human nicotinic acetylcholine receptor alpha4-beta2 at 10 uM
|
Homo sapiens
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation.
Year : 2005
Volume : 48
Issue : 10
First Page : 3474
Last Page : 3477
Authors : Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD, O'Neill BT.
Abstract : Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
|
Change in membrane potential in TE-671 cells expressing acetylcholine neuromuscular receptors
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors.
Year : 2005
Volume : 15
Issue : 4
First Page : 1221
Last Page : 1224
Authors : Fitch RW, Kaneko Y, Klaperski P, Daly JW, Seitz G, Gündisch D.
Abstract : A series of pyridone ring-modified derivatives of (7R,9S)-(-)-cytisine were evaluated for affinity and functional activity at neuromuscular alpha1beta1gammadelta, ganglionic alpha3beta4, and central neuronal alpha4beta2 subtypes of nicotinic receptors. Halogenation at the 3-position improved affinity and functional activity, while substitution at the 5-position led to modest decreases in both, and disubstitution led to near abolition of functional activities and could be correlated with the electron-withdrawing ability of the halogen. Subtype selectivities of the halogenated derivatives were altered relative to cytisine in a substitution-dependent manner. Caulophylline methiodide was less potent than cytisine, but retained significant activity. Thiocytisine was relatively weak in potency and efficacy, but was significantly selective for the alpha4beta2 subtype.
|
Change in membrane potential in K-177 cells expressing acetylcholine central neuronal receptor alpha4-beta2 subunits
|
Homo sapiens
|
0.42
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors.
Year : 2005
Volume : 15
Issue : 4
First Page : 1221
Last Page : 1224
Authors : Fitch RW, Kaneko Y, Klaperski P, Daly JW, Seitz G, Gündisch D.
Abstract : A series of pyridone ring-modified derivatives of (7R,9S)-(-)-cytisine were evaluated for affinity and functional activity at neuromuscular alpha1beta1gammadelta, ganglionic alpha3beta4, and central neuronal alpha4beta2 subtypes of nicotinic receptors. Halogenation at the 3-position improved affinity and functional activity, while substitution at the 5-position led to modest decreases in both, and disubstitution led to near abolition of functional activities and could be correlated with the electron-withdrawing ability of the halogen. Subtype selectivities of the halogenated derivatives were altered relative to cytisine in a substitution-dependent manner. Caulophylline methiodide was less potent than cytisine, but retained significant activity. Thiocytisine was relatively weak in potency and efficacy, but was significantly selective for the alpha4beta2 subtype.
|
Effective concentration in KXalpha-3-beta-4R2 cells expressing rat nicotinic acetylcholine receptor alpha3-beta4 subunits
|
Rattus norvegicus
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors.
Year : 2005
Volume : 15
Issue : 4
First Page : 1221
Last Page : 1224
Authors : Fitch RW, Kaneko Y, Klaperski P, Daly JW, Seitz G, Gündisch D.
Abstract : A series of pyridone ring-modified derivatives of (7R,9S)-(-)-cytisine were evaluated for affinity and functional activity at neuromuscular alpha1beta1gammadelta, ganglionic alpha3beta4, and central neuronal alpha4beta2 subtypes of nicotinic receptors. Halogenation at the 3-position improved affinity and functional activity, while substitution at the 5-position led to modest decreases in both, and disubstitution led to near abolition of functional activities and could be correlated with the electron-withdrawing ability of the halogen. Subtype selectivities of the halogenated derivatives were altered relative to cytisine in a substitution-dependent manner. Caulophylline methiodide was less potent than cytisine, but retained significant activity. Thiocytisine was relatively weak in potency and efficacy, but was significantly selective for the alpha4beta2 subtype.
|
Percent inhibition of 10 uM nicotine response in human Nicotinic acetylcholine receptor alpha4-beta2
|
Homo sapiens
|
30.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In pursuit of alpha4beta2 nicotinic receptor partial agonists for smoking cessation: carbon analogs of (-)-cytisine.
Year : 2005
Volume : 15
Issue : 12
First Page : 2974
Last Page : 2979
Authors : Coe JW, Vetelino MG, Bashore CG, Wirtz MC, Brooks PR, Arnold EP, Lebel LA, Fox CB, Sands SB, Davis TI, Schulz DW, Rollema H, Tingley FD, O'Neill BT.
Abstract : The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
|
Binding affinity for human Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK 293 cells using [3H]nicotine
|
Homo sapiens
|
0.23
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation.
Year : 2005
Volume : 15
Issue : 22
First Page : 4889
Last Page : 4897
Authors : Coe JW, Brooks PR, Wirtz MC, Bashore CG, Bianco KE, Vetelino MG, Arnold EP, Lebel LA, Fox CB, Tingley FD, Schulz DW, Davis TI, Sands SB, Mansbach RS, Rollema H, O'Neill BT.
Abstract : 3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
|
Binding affinity to human Nicotinic acetylcholine receptor alpha3-beta4 expressed in IMR32 cells using [3H]epibatidine
|
Homo sapiens
|
840.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation.
Year : 2005
Volume : 15
Issue : 22
First Page : 4889
Last Page : 4897
Authors : Coe JW, Brooks PR, Wirtz MC, Bashore CG, Bianco KE, Vetelino MG, Arnold EP, Lebel LA, Fox CB, Tingley FD, Schulz DW, Davis TI, Sands SB, Mansbach RS, Rollema H, O'Neill BT.
Abstract : 3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
|
Binding affinity to human Nicotinic acetylcholine receptor alpha-1-beta-gamma-delta expressed in HEK 293 cells using [3H]alpha-bungarotoxin
|
Homo sapiens
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation.
Year : 2005
Volume : 15
Issue : 22
First Page : 4889
Last Page : 4897
Authors : Coe JW, Brooks PR, Wirtz MC, Bashore CG, Bianco KE, Vetelino MG, Arnold EP, Lebel LA, Fox CB, Tingley FD, Schulz DW, Davis TI, Sands SB, Mansbach RS, Rollema H, O'Neill BT.
Abstract : 3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
|
Percent inhibition against 10 uM nicotine binding to human Nicotinic acetylcholine receptor alpha4-beta2 expressed in Xenopus oocytes at 10 uM
|
Homo sapiens
|
30.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation.
Year : 2005
Volume : 15
Issue : 22
First Page : 4889
Last Page : 4897
Authors : Coe JW, Brooks PR, Wirtz MC, Bashore CG, Bianco KE, Vetelino MG, Arnold EP, Lebel LA, Fox CB, Tingley FD, Schulz DW, Davis TI, Sands SB, Mansbach RS, Rollema H, O'Neill BT.
Abstract : 3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
|
Displacement of [3H]epibatidine from rat alpha-2-beta-2 nACHR expressed in human HEK293 cells
|
Rattus norvegicus
|
1.07
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity.
Year : 2006
Volume : 49
Issue : 9
First Page : 2673
Last Page : 2676
Authors : Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP.
Abstract : We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
|
Displacement of [3H]epibatidine from rat alpha-2-beta-4 nACHR expressed in human HEK293 cells
|
Rattus norvegicus
|
5.41
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity.
Year : 2006
Volume : 49
Issue : 9
First Page : 2673
Last Page : 2676
Authors : Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP.
Abstract : We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
|
Displacement of [3H]epibatidine from rat alpha-3-beta-2 nACHR expressed in human HEK293 cells
|
Rattus norvegicus
|
37.2
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity.
Year : 2006
Volume : 49
Issue : 9
First Page : 2673
Last Page : 2676
Authors : Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP.
Abstract : We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
|
Displacement of [3H]epibatidine from rat alpha3beta4 nACHR expressed in human HEK293 cells
|
Rattus norvegicus
|
217.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity.
Year : 2006
Volume : 49
Issue : 9
First Page : 2673
Last Page : 2676
Authors : Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP.
Abstract : We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
|
Displacement of [3H]epibatidine from rat alpha-4-beta-2 nACHR expressed in human HEK293 cells
|
Rattus norvegicus
|
1.51
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity.
Year : 2006
Volume : 49
Issue : 9
First Page : 2673
Last Page : 2676
Authors : Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP.
Abstract : We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
|
Displacement of [3H]epibatidine from rat alpha-4-beta-4 nACHR expressed in human HEK293 cells
|
Rattus norvegicus
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity.
Year : 2006
Volume : 49
Issue : 9
First Page : 2673
Last Page : 2676
Authors : Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP.
Abstract : We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
|
Displacement of [3H]epibatidine from rat forebrain alpha4beta2 nACHR
|
Rattus norvegicus
|
1.92
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity.
Year : 2006
Volume : 49
Issue : 9
First Page : 2673
Last Page : 2676
Authors : Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP.
Abstract : We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
|
Selectivity for rat alpha-4-beta-2 nACHR over alpha3beta4 nACHR expressed in human HEK293 cells
|
Rattus norvegicus
|
144.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity.
Year : 2006
Volume : 49
Issue : 9
First Page : 2673
Last Page : 2676
Authors : Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP.
Abstract : We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
|
Displacement of [3H]epibatidine from human recombinant alpha4beta2 nAChR in HEK293 cells by SPA assay
|
Homo sapiens
|
2.59
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Epibatidine isomers and analogues: structure-activity relationships.
Year : 2006
Volume : 16
Issue : 21
First Page : 5493
Last Page : 5497
Authors : White R, Malpass JR, Handa S, Richard Baker S, Broad LM, Folly L, Mogg A.
Abstract : Binding affinities for a range of epibatidine isomers and analogues at the alpha4beta2 and alpha3beta4 nAChR subtypes are reported; compounds having similar N-N distances to epibatidine show similar, high potencies.
|
Displacement of [3H]epibatidine from human recombinant alpha-3-beta-4 nAChR in HEK293 cells by SPA assay
|
Homo sapiens
|
525.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Epibatidine isomers and analogues: structure-activity relationships.
Year : 2006
Volume : 16
Issue : 21
First Page : 5493
Last Page : 5497
Authors : White R, Malpass JR, Handa S, Richard Baker S, Broad LM, Folly L, Mogg A.
Abstract : Binding affinities for a range of epibatidine isomers and analogues at the alpha4beta2 and alpha3beta4 nAChR subtypes are reported; compounds having similar N-N distances to epibatidine show similar, high potencies.
|
Displacement of [3H]nicotine from alpha4beta2 nAChR in Sprague-Dawley rat brain membrane
|
Rattus norvegicus
|
0.43
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Deconstructing cytisine: The syntheses of (+/-)-cyfusine and (+/-)-cyclopropylcyfusine, fused ring analogs of cytisine.
Year : 2008
Volume : 18
Issue : 7
First Page : 2316
Last Page : 2319
Authors : Yohannes D, Procko K, Lebel LA, Fox CB, O'Neill BT.
Abstract : A novel fused tricyclic analog (11) of cytisine has been prepared (coined 'cyfusine') and determined to have high affinity at neuronal nicotinic acetylcholine receptors. A [3+2] cycloaddition protocol permitted entry into a 3,4-differentially difunctionalized dihydropyrrole (7). The penultimate cyclization was accomplished using the modified Van Tamelen conditions developed in our earlier synthesis of (+/-)-cytisine. Sequential ring-forming reactions ([3+2] cycloaddition/cyclopropanation/pyridone cyclization) gives a unique cyclopropyl analog (16) possessing a skeleton isoatomic with that of cytisine.
|
Displacement of [3H]nicotin from nicotinic ACh receptor
|
None
|
140.0
nM
|
|
Journal : J. Nat. Prod.
Title : Binding of quinolizidine alkaloids to nicotinic and muscarinic acetylcholine receptors.
Year : 1994
Volume : 57
Issue : 9
First Page : 1316
Last Page : 1319
Authors : Schmeller T, Sauerwein M, Sporer F, Wink M, Müller WE.
Abstract : Fourteen quinolizidine alkaloids, isolated from Lupinus albus, L. mutabilis, and Anagyris foetida, were analyzed for their affinity for nicotinic and/or muscarinic acetylcholine receptors. Of the compounds tested, the alpha-pyridones, N-methylcytisine and cytisine, showed the highest affinities at the nicotinic receptor, while several quinolizidine alkaloid types were especially active at the muscarinic receptor.
|
Displacement of (+/-)-[3H]epibatidine from alpha4beta2 nicotinic acetylcholine receptor in rat brain cortex membrane homogenates
|
Rattus norvegicus
|
0.48
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, binding, and modeling studies of new cytisine derivatives, as ligands for neuronal nicotinic acetylcholine receptor subtypes.
Year : 2009
Volume : 52
Issue : 14
First Page : 4345
Last Page : 4357
Authors : Tasso B, Canu Boido C, Terranova E, Gotti C, Riganti L, Clementi F, Artali R, Bombieri G, Meneghetti F, Sparatore F.
Abstract : The availability of drug affecting neuronal nicotinic acetylcholine receptors (nAChRs) may have important therapeutic potential for the treatment of several CNS pathologies. Pursuing our efforts on the systematic structural modification of cytisine and N-arylalkyl and N-aroylalkyl cytisines were synthesized and tested for the displacement of [(3)H]-epibatidine and [(125)I]-alpha-bungarotoxin from the most widespread brain nAChRs subtypes alpha(4)beta(2) and alpha(7), respectively. While the affinity for alpha(7) subtype was rather poor (K(i) from 0.4 to >50 microM), the affinity for alpha(4)beta(2) subtype was very interesting, with nanomolar K(i) values for the best compounds. The N-substituted cytisines were docked into the rat and human alpha(4)beta(2) nAChR models based on the extracellular domain of a molluscan acetylcholine binding protein. The docking results agreed with the binding data, allowing the detection of discrete amino acid residues of the alpha and beta subunits essential for the ligand binding on rat and human nAChRs, providing a novel structural framework for the development of new alpha(4)beta(2) selective ligands.
|
Displacement of [125I]alpha-bungarotoxin from alpha7 nicotinic acetylcholine receptor in rat brain cortex membrane homogenates
|
Rattus norvegicus
|
331.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, binding, and modeling studies of new cytisine derivatives, as ligands for neuronal nicotinic acetylcholine receptor subtypes.
Year : 2009
Volume : 52
Issue : 14
First Page : 4345
Last Page : 4357
Authors : Tasso B, Canu Boido C, Terranova E, Gotti C, Riganti L, Clementi F, Artali R, Bombieri G, Meneghetti F, Sparatore F.
Abstract : The availability of drug affecting neuronal nicotinic acetylcholine receptors (nAChRs) may have important therapeutic potential for the treatment of several CNS pathologies. Pursuing our efforts on the systematic structural modification of cytisine and N-arylalkyl and N-aroylalkyl cytisines were synthesized and tested for the displacement of [(3)H]-epibatidine and [(125)I]-alpha-bungarotoxin from the most widespread brain nAChRs subtypes alpha(4)beta(2) and alpha(7), respectively. While the affinity for alpha(7) subtype was rather poor (K(i) from 0.4 to >50 microM), the affinity for alpha(4)beta(2) subtype was very interesting, with nanomolar K(i) values for the best compounds. The N-substituted cytisines were docked into the rat and human alpha(4)beta(2) nAChR models based on the extracellular domain of a molluscan acetylcholine binding protein. The docking results agreed with the binding data, allowing the detection of discrete amino acid residues of the alpha and beta subunits essential for the ligand binding on rat and human nAChRs, providing a novel structural framework for the development of new alpha(4)beta(2) selective ligands.
|
Displacement of [3H]cytisine from alpha4beta2 nicotinic acetylcholine receptor in rat brain cortex membrane homogenates
|
Rattus norvegicus
|
0.34
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, binding, and modeling studies of new cytisine derivatives, as ligands for neuronal nicotinic acetylcholine receptor subtypes.
Year : 2009
Volume : 52
Issue : 14
First Page : 4345
Last Page : 4357
Authors : Tasso B, Canu Boido C, Terranova E, Gotti C, Riganti L, Clementi F, Artali R, Bombieri G, Meneghetti F, Sparatore F.
Abstract : The availability of drug affecting neuronal nicotinic acetylcholine receptors (nAChRs) may have important therapeutic potential for the treatment of several CNS pathologies. Pursuing our efforts on the systematic structural modification of cytisine and N-arylalkyl and N-aroylalkyl cytisines were synthesized and tested for the displacement of [(3)H]-epibatidine and [(125)I]-alpha-bungarotoxin from the most widespread brain nAChRs subtypes alpha(4)beta(2) and alpha(7), respectively. While the affinity for alpha(7) subtype was rather poor (K(i) from 0.4 to >50 microM), the affinity for alpha(4)beta(2) subtype was very interesting, with nanomolar K(i) values for the best compounds. The N-substituted cytisines were docked into the rat and human alpha(4)beta(2) nAChR models based on the extracellular domain of a molluscan acetylcholine binding protein. The docking results agreed with the binding data, allowing the detection of discrete amino acid residues of the alpha and beta subunits essential for the ligand binding on rat and human nAChRs, providing a novel structural framework for the development of new alpha(4)beta(2) selective ligands.
|
Displacement of [3H]epibatidine from rat alpha4beta2 nAChR
|
Rattus norvegicus
|
69.18
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In silico characterization of cytisinoids docked into an acetylcholine binding protein.
Year : 2010
Volume : 20
Issue : 12
First Page : 3683
Last Page : 3687
Authors : Abin-Carriquiry JA, Zunini MP, Cassels BK, Wonnacott S, Dajas F.
Abstract : Homology models of nicotinic acetylcholine receptors (nAChRs) suggest that subtype specificity is due to non-conserved residues in the complementary subunit of the ligand-binding pocket. Cytisine and its derivatives generally show a strong preference for heteromeric alpha4beta2* nAChRs over the homomeric alpha7 subtype, and the structural modifications studied do not cause large changes in their nAChR subtype selectivity. In the present work we docked cytisine, N-methylcytisine, and several pyridone ring-substituted cytisinoids into the crystallographic structure of the Lymnaea stagnalis acetylcholine binding protein (AChBP) co-crystallized with nicotine (1UW6). The graphical analysis of the best poses showed that cytisinoids have weak interactions with the side chains of the non-conserved amino acids in the complementary subunit justifying the use of PDB 1UWB as a surrogate for nAChR. Furthermore, we found a high correlation (R(2)=0.96) between the experimental pIC(50) values at alpha4beta2* nAChR and docking energy (S) of the best cytisinoid poses within the AChBP. Due to the quality of the correlation we suggest that this equation might be used as a predictive model to propose new cytisine-derived nAChRs ligands. Our docking results also suggest that further structural modifications of these cytisinoids will not greatly alter their alpha4beta2*/alpha7 selectivity.
|
Displacement of (+/-)-[3H]epibatidine from alpha4beta2 nAChR in rat cortical membrane
|
Rattus norvegicus
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes.
Year : 2010
Volume : 18
Issue : 12
First Page : 4498
Last Page : 4508
Authors : Dallanoce C, Frigerio F, Martelli G, Grazioso G, Matera C, Pomè DY, Pucci L, Clementi F, Gotti C, De Amici M.
Abstract : A group of novel tricyclic Delta(2)-isoxazolines (4b, 5b, 7a-b, and 8a-b) and 3-oxo-isoxazolidines (6a-b and 9a-b), structurally related to cytisine or norferruginine, was prepared through 1,3-dipolar cycloadditions involving suitable olefins and bromonitrile oxide. The target compounds were assayed at alpha4beta2 and alpha7 neuronal acetylcholine receptors (nAChRs). The results of competition binding experiments indicated for the new derivatives a reduction of the affinity at the alpha4beta2 subtype in comparison with the reference molecules, coupled with an overall negligible affinity at the alpha7 subtype. The binding mode of the bromo-Delta(2)-isoxazolines 4b and 7b, which were the highest affinity ligands in the series (K(i)=0.92 and 0.75 microM, respectively), was analyzed by applying a recently developed model of the alpha4beta2 nAChRs.
|
Displacement of [125I]alpha-Bungarotoxin from alpha7 nAChR in rat cortical membrane
|
Rattus norvegicus
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes.
Year : 2010
Volume : 18
Issue : 12
First Page : 4498
Last Page : 4508
Authors : Dallanoce C, Frigerio F, Martelli G, Grazioso G, Matera C, Pomè DY, Pucci L, Clementi F, Gotti C, De Amici M.
Abstract : A group of novel tricyclic Delta(2)-isoxazolines (4b, 5b, 7a-b, and 8a-b) and 3-oxo-isoxazolidines (6a-b and 9a-b), structurally related to cytisine or norferruginine, was prepared through 1,3-dipolar cycloadditions involving suitable olefins and bromonitrile oxide. The target compounds were assayed at alpha4beta2 and alpha7 neuronal acetylcholine receptors (nAChRs). The results of competition binding experiments indicated for the new derivatives a reduction of the affinity at the alpha4beta2 subtype in comparison with the reference molecules, coupled with an overall negligible affinity at the alpha7 subtype. The binding mode of the bromo-Delta(2)-isoxazolines 4b and 7b, which were the highest affinity ligands in the series (K(i)=0.92 and 0.75 microM, respectively), was analyzed by applying a recently developed model of the alpha4beta2 nAChRs.
|
Displacement of [3H]cytisine from rat alpha4beta2 nAChR in rat brain cell membrane
|
Rattus norvegicus
|
1.06
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of 9-fluoro substituted (-)-cytisine derivatives as ligands with high affinity for nicotinic receptors.
Year : 2010
Volume : 20
Issue : 22
First Page : 6667
Last Page : 6670
Authors : Houllier N, Gopisetti J, Lestage P, Lasne MC, Rouden J.
Abstract : (-)-9-Fluorocytisine, (-)-9-methylcytisine and (-)-9-trifluoromethylcytisine were synthesized from the natural product (-)-cytisine. 9-Methyl and 9-trifluoromethyl cytisines display a remarkable affinity at the α(4)β(2) nicotinic receptor subtype (0.2 nM) with a high selectivity versus the α(7) nAChR subtype. Comparison of the affinity values suggests that the size of the substituent at the 9 position of (-)-cytisine seems more important than electronic factors for efficient binding and selectivity at α(4)β(2) nAChRs.
|
Displacement of [3H]epibatidine from rat alpha3beta4 nAChR expressed in HEK292 cells after 3 hrs
|
Rattus norvegicus
|
203.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel α3β4 nicotinic acetylcholine receptor-selective ligands. Discovery, structure-activity studies, and pharmacological evaluation.
Year : 2010
Volume : 53
Issue : 22
First Page : 8187
Last Page : 8191
Authors : Zaveri N, Jiang F, Olsen C, Polgar W, Toll L.
Abstract : Antagonist activity at the α3β4 nicotinic acetylcholine receptor (nAChR) is thought to contribute to the antiaddictive properties of several compounds. However, truly selective ligands for the α3β4 nAChR have not been available. We report the discovery and SAR of a novel class of compounds that bind to the α3β4 nAChR and have no measurable affinity for the α4β2 or α7 subtype. In functional assays the lead compound antagonized epibatidine-induced Ca(2+) flux in α3β4-transfected cells in a noncompetitive manner.
|
Displacement of [3H]epibatidine from rat alpha4beta2 nAChR expressed in HEK292 cells after 3 hrs
|
Rattus norvegicus
|
1.53
nM
|
|
Journal : J. Med. Chem.
Title : Novel α3β4 nicotinic acetylcholine receptor-selective ligands. Discovery, structure-activity studies, and pharmacological evaluation.
Year : 2010
Volume : 53
Issue : 22
First Page : 8187
Last Page : 8191
Authors : Zaveri N, Jiang F, Olsen C, Polgar W, Toll L.
Abstract : Antagonist activity at the α3β4 nicotinic acetylcholine receptor (nAChR) is thought to contribute to the antiaddictive properties of several compounds. However, truly selective ligands for the α3β4 nAChR have not been available. We report the discovery and SAR of a novel class of compounds that bind to the α3β4 nAChR and have no measurable affinity for the α4β2 or α7 subtype. In functional assays the lead compound antagonized epibatidine-induced Ca(2+) flux in α3β4-transfected cells in a noncompetitive manner.
|
Inhibition of electric eel AChE at 2 mg/ml by Ellman's method
|
Electrophorus electricus
|
2.17
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Inhibition of horse BChE at 2 mg/ml by Ellman's method
|
Equus caballus
|
-3.85
%
|
|
Journal : Bioorg. Med. Chem.
Title : Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: the case of chelerythrine.
Year : 2012
Volume : 20
Issue : 22
First Page : 6669
Last Page : 6679
Authors : Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez A, Shinde P, Gopi Mohan C, Vuorela P.
Abstract : The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
|
Binding affinity to rat alpha4beta2 nAChR
|
Rattus norvegicus
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity studies of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes: a novel class of highly potent nicotinic receptor ligands.
Year : 2012
Volume : 55
Issue : 22
First Page : 9929
Last Page : 9945
Authors : Breining SR, Melvin M, Bhatti BS, Byrd GD, Kiser MN, Hepler CD, Hooker DN, Zhang J, Reynolds LA, Benson LR, Fedorov NB, Sidach SS, Mitchener JP, Lucero LM, Lukas RJ, Whiteaker P, Yohannes D.
Abstract : The potential for nicotinic ligands with affinity for the α4β2 or α7 subtypes to treat such diverse diseases as nicotine addiction, neuropathic pain, and neurodegenerative and cognitive disorders has been exhibited clinically for several compounds while preclinical activity in relevant in vivo models has been demonstrated for many more. For several therapeutic programs, we sought nicotinic ligands with various combinations of affinity and function across both subtypes, with an emphasis on dual α4β2-α7 ligands, to explore the possibility of synergistic effects. We report here the structure-activity relationships (SAR) for a novel series of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes and characterize many of the analogues for activity at multiple nicotinic subtypes.
|
Displacement of [3H]alpha-bungarotoxin from nAChR in honeybee head membrane after 60 min by scintillation counting
|
Apis mellifera
|
650.0
nM
|
|
Journal : J Pesticide Sci
Title : Binding of Nicotinoids and the Related Compounds to the Insect Nicotinic Acetyicholine Receptor
Year : 1992
Volume : 17
Issue : 4
First Page : 231
Last Page : 236
Authors : TOMIZAWA M, YAMAMOTO I
|
Displacement of [3H]PCP from nAChR in Apis mellifera (honeybee) head homogenates at 1000 uM
|
Apis mellifera
|
12.6
%
|
|
Journal : J Pesticide Sci
Title : Pharmacological Characteristics of Insect Nicotinic Acetyicholine Receptor with Its Ion Channel and the Comparison of the Effect of Nicotinoids and Neonicotinoids
Year : 1995
Volume : 20
Issue : 1
First Page : 57
Last Page : 64
Authors : TOMIZAWA M, OTSUKA H, MIYAMOTO T, ELDEFRAWI ME, YAMAMOTO I
|
Displacement of [3H]alpha-BGT from nAChR in Apis mellifera (honeybee) head homogenates
|
Apis mellifera
|
267.0
nM
|
|
Journal : J Pesticide Sci
Title : Pharmacological Characteristics of Insect Nicotinic Acetyicholine Receptor with Its Ion Channel and the Comparison of the Effect of Nicotinoids and Neonicotinoids
Year : 1995
Volume : 20
Issue : 1
First Page : 57
Last Page : 64
Authors : TOMIZAWA M, OTSUKA H, MIYAMOTO T, ELDEFRAWI ME, YAMAMOTO I
|
Displacement of [125I]alpha-bungarotoxin from alpha7 nAChR from rat hippocampus
|
Rattus norvegicus
|
230.0
nM
|
|
Journal : J. Nat. Prod.
Title : (+)-Laburnamine, a natural selective ligand and partial agonist for the α4β2 nicotinic receptor subtype.
Year : 2013
Volume : 76
Issue : 4
First Page : 727
Last Page : 731
Authors : Tasso B, Novelli F, Sparatore F, Fasoli F, Gotti C.
Abstract : (+)-Laburnamine (1), a rare alkaloid extracted from Laburnum anagyroides seeds (∼4 mg from 1 kg), was shown to bind with high affinity (Ki, 293 nM) to the α4β2 nicotinic receptor subtype, which is, respectively, 126 and 136 times higher than to the α3β4 (Ki 37 μM) and α7 subtypes (Ki 40 μM). When its ability to release [(3)H]-dopamine from striatal slices was tested in a functional assay, compound 1 behaved as a partial agonist with an EC50 of 5.8 μM and an Emax that was 43% that of nicotine. When incubated with nicotine in the same assay, 1 prevented a maximal effect from being reached.
|
Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK cells
|
Homo sapiens
|
280.0
nM
|
|
Journal : J. Nat. Prod.
Title : (+)-Laburnamine, a natural selective ligand and partial agonist for the α4β2 nicotinic receptor subtype.
Year : 2013
Volume : 76
Issue : 4
First Page : 727
Last Page : 731
Authors : Tasso B, Novelli F, Sparatore F, Fasoli F, Gotti C.
Abstract : (+)-Laburnamine (1), a rare alkaloid extracted from Laburnum anagyroides seeds (∼4 mg from 1 kg), was shown to bind with high affinity (Ki, 293 nM) to the α4β2 nicotinic receptor subtype, which is, respectively, 126 and 136 times higher than to the α3β4 (Ki 37 μM) and α7 subtypes (Ki 40 μM). When its ability to release [(3)H]-dopamine from striatal slices was tested in a functional assay, compound 1 behaved as a partial agonist with an EC50 of 5.8 μM and an Emax that was 43% that of nicotine. When incubated with nicotine in the same assay, 1 prevented a maximal effect from being reached.
|
Displacement of [3H]epibatidine from alpha4beta2 nAChR in rat cortex
|
Rattus norvegicus
|
2.1
nM
|
|
Journal : J. Nat. Prod.
Title : (+)-Laburnamine, a natural selective ligand and partial agonist for the α4β2 nicotinic receptor subtype.
Year : 2013
Volume : 76
Issue : 4
First Page : 727
Last Page : 731
Authors : Tasso B, Novelli F, Sparatore F, Fasoli F, Gotti C.
Abstract : (+)-Laburnamine (1), a rare alkaloid extracted from Laburnum anagyroides seeds (∼4 mg from 1 kg), was shown to bind with high affinity (Ki, 293 nM) to the α4β2 nicotinic receptor subtype, which is, respectively, 126 and 136 times higher than to the α3β4 (Ki 37 μM) and α7 subtypes (Ki 40 μM). When its ability to release [(3)H]-dopamine from striatal slices was tested in a functional assay, compound 1 behaved as a partial agonist with an EC50 of 5.8 μM and an Emax that was 43% that of nicotine. When incubated with nicotine in the same assay, 1 prevented a maximal effect from being reached.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
99.71
%
|
|
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
|
106.19
%
|
|
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]methyllycaconitine from Sprague-Dawley rat brain alpha7 nAChR after 120 mins by liquid scintillation counting analysis
|
Rattus norvegicus
|
261.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs.
Year : 2013
Volume : 21
Issue : 23
First Page : 7309
Last Page : 7329
Authors : Eibl C, Munoz L, Tomassoli I, Stokes C, Papke RL, Gündisch D.
Abstract : 3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2(∗) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β2(∗) nAChR. All evaluated compounds are partial agonists or antagonists at α4β2(∗), with reduced or no effects on α3β4(∗) with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.
|
Displacement of [3H]epibatidine from calf adrenal alpha3beta4 nAChR after 90 mins by liquid scintillation counting analysis
|
Bos taurus
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs.
Year : 2013
Volume : 21
Issue : 23
First Page : 7309
Last Page : 7329
Authors : Eibl C, Munoz L, Tomassoli I, Stokes C, Papke RL, Gündisch D.
Abstract : 3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2(∗) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β2(∗) nAChR. All evaluated compounds are partial agonists or antagonists at α4β2(∗), with reduced or no effects on α3β4(∗) with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.
|
Displacement of [3H]epibatidine from Sprague-Dawley rat brain alpha4beta2 nAChR after 90 mins by liquid scintillation counting analysis
|
Rattus norvegicus
|
0.122
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs.
Year : 2013
Volume : 21
Issue : 23
First Page : 7309
Last Page : 7329
Authors : Eibl C, Munoz L, Tomassoli I, Stokes C, Papke RL, Gündisch D.
Abstract : 3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2(∗) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β2(∗) nAChR. All evaluated compounds are partial agonists or antagonists at α4β2(∗), with reduced or no effects on α3β4(∗) with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.
|
Displacement of [3H]methyllycaconitine from rat forebrain alpha7 nAChR
|
Rattus norvegicus
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: the influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents.
Year : 2013
Volume : 21
Issue : 23
First Page : 7283
Last Page : 7308
Authors : Eibl C, Tomassoli I, Munoz L, Stokes C, Papke RL, Gündisch D.
Abstract : 3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β2(∗) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β2(∗) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.
|
Binding affinity to pig adrenal alpha3beta4 nAChR by radioligand displacement assay
|
Sus scrofa
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: the influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents.
Year : 2013
Volume : 21
Issue : 23
First Page : 7283
Last Page : 7308
Authors : Eibl C, Tomassoli I, Munoz L, Stokes C, Papke RL, Gündisch D.
Abstract : 3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β2(∗) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β2(∗) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.
|
Displacement of [3H]-epibatidine from rat forebrain alpha4beta2 nAChR
|
Rattus norvegicus
|
0.122
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: the influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents.
Year : 2013
Volume : 21
Issue : 23
First Page : 7283
Last Page : 7308
Authors : Eibl C, Tomassoli I, Munoz L, Stokes C, Papke RL, Gündisch D.
Abstract : 3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β2(∗) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β2(∗) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.
|
Partial agonist activity at alpha4beta2 nAChR (unknown origin)
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors.
Year : 2014
Volume : 57
Issue : 20
First Page : 8204
Last Page : 8223
Authors : Yu LF, Zhang HK, Caldarone BJ, Eaton JB, Lukas RJ, Kozikowski AP.
Abstract : Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.
|
Partial agonist activity at alpha3beta4 nAChR (unknown origin)
|
Homo sapiens
|
480.0
nM
|
|
Journal : J. Med. Chem.
Title : Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors.
Year : 2014
Volume : 57
Issue : 20
First Page : 8204
Last Page : 8223
Authors : Yu LF, Zhang HK, Caldarone BJ, Eaton JB, Lukas RJ, Kozikowski AP.
Abstract : Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.
|
Inactivation of alpha4beta2* nAChR high affinity site (unknown origin) expressed in xenopus oocytes by electrophysiology method
|
Homo sapiens
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors.
Year : 2014
Volume : 57
Issue : 20
First Page : 8204
Last Page : 8223
Authors : Yu LF, Zhang HK, Caldarone BJ, Eaton JB, Lukas RJ, Kozikowski AP.
Abstract : Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.
|
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
|
5.71
%
|
|
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.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
20.97
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.59
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-2.316
%
|
|
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.
|
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
|
Chlorocebus sabaeus
|
0.12
%
|
|
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
|
Chlorocebus sabaeus
|
-0.04
%
|
|
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
|
Chlorocebus sabaeus
|
-0.12
%
|
|
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
|
Chlorocebus sabaeus
|
-0.04
%
|
|
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
|
Chlorocebus sabaeus
|
-0.12
%
|
|
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
|
Chlorocebus sabaeus
|
0.12
%
|
|
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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Displacement of [3H]cytisine from human alpha4beta2 nAChR by Cheng-Prusoff equation analysis
|
Homo sapiens
|
0.28
nM
|
|
Journal : Bioorg Med Chem
Title : Pyridine alkaloids with activity in the central nervous system.
Year : 2020
Volume : 28
Issue : 24
First Page : 115820
Last Page : 115820
Authors : Lin SX,Curtis MA,Sperry J
Abstract : This review discusses all pyridine alkaloids with CNS activity, their therapeutic potential, and the interesting array of sources whence they originate.
|
Displacement of [3H]nicotine from rat alpha4beta2 nAChR by liquid scintillation counting
|
Rattus norvegicus
|
0.4
nM
|
|
Journal : Bioorg Med Chem
Title : Pyridine alkaloids with activity in the central nervous system.
Year : 2020
Volume : 28
Issue : 24
First Page : 115820
Last Page : 115820
Authors : Lin SX,Curtis MA,Sperry J
Abstract : This review discusses all pyridine alkaloids with CNS activity, their therapeutic potential, and the interesting array of sources whence they originate.
|
Displacement of [3H]Cytisine from Sprague-Dawley rat brain nAChR
|
Rattus norvegicus
|
0.16
nM
|
|
Journal : Bioorg Med Chem
Title : Pyridine alkaloids with activity in the central nervous system.
Year : 2020
Volume : 28
Issue : 24
First Page : 115820
Last Page : 115820
Authors : Lin SX,Curtis MA,Sperry J
Abstract : This review discusses all pyridine alkaloids with CNS activity, their therapeutic potential, and the interesting array of sources whence they originate.
|
Binding affinity to Sprague-Dawley rat brain nAChR incubated for 75 min by scatchard analysis
|
Rattus norvegicus
|
0.145
nM
|
|
Journal : Bioorg Med Chem
Title : Pyridine alkaloids with activity in the central nervous system.
Year : 2020
Volume : 28
Issue : 24
First Page : 115820
Last Page : 115820
Authors : Lin SX,Curtis MA,Sperry J
Abstract : This review discusses all pyridine alkaloids with CNS activity, their therapeutic potential, and the interesting array of sources whence they originate.
