|
Displacement of [3H]ketanserin from 5-hydroxytryptamine 2A receptor expressed NIH3T3 cells
|
None
|
160.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Influence of chain length and N-alkylation on the selective serotonin receptor ligand 9-(aminomethyl)-9,10-dihydroanthracene.
Year : 2001
Volume : 11
Issue : 5
First Page : 655
Last Page : 658
Authors : Runyon SP, Savage JE, Taroua M, Roth BL, Glennon RA, Westkaemper RB.
Abstract : Comparison of the serotonin 5-HT2A receptor affinities of chain lengthened and N-alkylated analogues of the novel ligand 9-aminomethyl-9,10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine imipramine suggests that the two agents bind to the receptor in different fashions. The demonstration that AMDA is highly selective for serotonin receptors (5-HT2A, K = 20nM; 5-HT2C, Ki=43nM) versus the dopamine D2 receptor (Ki>10,000nM), as well as the serotonin and norepinephrine transporters (Ki>10,000nM) further suggests that AMDA and the nonselective ligand imipramine interact with these target macromolecules in different ways.
|
Compound was tested for its inhibitory activity against 5-hydroxytryptamine receptor
|
Rattus norvegicus
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of predictive retention-activity relationship models of tricyclic antidepressants by micellar liquid chromatography.
Year : 1999
Volume : 42
Issue : 16
First Page : 3154
Last Page : 3162
Authors : Quiñones-Torrelo C, Sagrado S, Villanueva-Camañas RM, Medina-Hernández MJ.
Abstract : The distribution of tricyclic antidepressants from plasma to brain, where these drugs exert their main clinical action, and other organs is related to transport events across the cell membranes of the different tissues. It could be expected that all the molecular features that condition the transport processes (mainly hydrophobicity and molar total charge) also control the pharmacokinetic and biochemical behavior. Micellar liquid chromatography (MLC) has been proposed to emulate in vitro the partitioning process in the biomembranes. The use of micellar solutions of Brij35 as mobile phases in reversed-phase liquid chromatography has proven to be valid to predict the biological activities of local anesthetics, barbiturates, catecholamines, and benzodiazepines. In this paper, the relationships between the capacity factor in MLC and some pharmacokinetic parameters and biological responses of tricyclic antidepressants are studied. Predictive regression models for the estimation of these parameter values, using the logarithm of the retention data (log k) as independent variable, are also proposed.
|
Compound was tested for its binding affinity towards brain (Hippocampus) Adenylate cyclase
|
Cavia porcellus
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of predictive retention-activity relationship models of tricyclic antidepressants by micellar liquid chromatography.
Year : 1999
Volume : 42
Issue : 16
First Page : 3154
Last Page : 3162
Authors : Quiñones-Torrelo C, Sagrado S, Villanueva-Camañas RM, Medina-Hernández MJ.
Abstract : The distribution of tricyclic antidepressants from plasma to brain, where these drugs exert their main clinical action, and other organs is related to transport events across the cell membranes of the different tissues. It could be expected that all the molecular features that condition the transport processes (mainly hydrophobicity and molar total charge) also control the pharmacokinetic and biochemical behavior. Micellar liquid chromatography (MLC) has been proposed to emulate in vitro the partitioning process in the biomembranes. The use of micellar solutions of Brij35 as mobile phases in reversed-phase liquid chromatography has proven to be valid to predict the biological activities of local anesthetics, barbiturates, catecholamines, and benzodiazepines. In this paper, the relationships between the capacity factor in MLC and some pharmacokinetic parameters and biological responses of tricyclic antidepressants are studied. Predictive regression models for the estimation of these parameter values, using the logarithm of the retention data (log k) as independent variable, are also proposed.
|
Compound was tested for its binding affinity towards brain (neocortex) Adenylate cyclase
|
Cavia porcellus
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of predictive retention-activity relationship models of tricyclic antidepressants by micellar liquid chromatography.
Year : 1999
Volume : 42
Issue : 16
First Page : 3154
Last Page : 3162
Authors : Quiñones-Torrelo C, Sagrado S, Villanueva-Camañas RM, Medina-Hernández MJ.
Abstract : The distribution of tricyclic antidepressants from plasma to brain, where these drugs exert their main clinical action, and other organs is related to transport events across the cell membranes of the different tissues. It could be expected that all the molecular features that condition the transport processes (mainly hydrophobicity and molar total charge) also control the pharmacokinetic and biochemical behavior. Micellar liquid chromatography (MLC) has been proposed to emulate in vitro the partitioning process in the biomembranes. The use of micellar solutions of Brij35 as mobile phases in reversed-phase liquid chromatography has proven to be valid to predict the biological activities of local anesthetics, barbiturates, catecholamines, and benzodiazepines. In this paper, the relationships between the capacity factor in MLC and some pharmacokinetic parameters and biological responses of tricyclic antidepressants are studied. Predictive regression models for the estimation of these parameter values, using the logarithm of the retention data (log k) as independent variable, are also proposed.
|
Compound was tested for its inhibitory activity against Alpha-1 adrenergic receptor
|
None
|
0.25
nM
|
|
Journal : J. Med. Chem.
Title : Development of predictive retention-activity relationship models of tricyclic antidepressants by micellar liquid chromatography.
Year : 1999
Volume : 42
Issue : 16
First Page : 3154
Last Page : 3162
Authors : Quiñones-Torrelo C, Sagrado S, Villanueva-Camañas RM, Medina-Hernández MJ.
Abstract : The distribution of tricyclic antidepressants from plasma to brain, where these drugs exert their main clinical action, and other organs is related to transport events across the cell membranes of the different tissues. It could be expected that all the molecular features that condition the transport processes (mainly hydrophobicity and molar total charge) also control the pharmacokinetic and biochemical behavior. Micellar liquid chromatography (MLC) has been proposed to emulate in vitro the partitioning process in the biomembranes. The use of micellar solutions of Brij35 as mobile phases in reversed-phase liquid chromatography has proven to be valid to predict the biological activities of local anesthetics, barbiturates, catecholamines, and benzodiazepines. In this paper, the relationships between the capacity factor in MLC and some pharmacokinetic parameters and biological responses of tricyclic antidepressants are studied. Predictive regression models for the estimation of these parameter values, using the logarithm of the retention data (log k) as independent variable, are also proposed.
|
In vitro competitive binding versus [N-methyl-3H]WIN-35428 in murine kidney cells transfected with cDNA for human dopamine transporter (DAT)
|
None
|
0.49
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and characterization of iodine-123 labeled 2beta-carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane. A ligand for in vivo imaging of serotonin transporters by single-photon-emission tomography.
Year : 2003
Volume : 46
Issue : 6
First Page : 925
Last Page : 935
Authors : Goodman MM, Chen P, Plisson C, Martarello L, Galt J, Votaw JR, Kilts CD, Malveaux G, Camp VM, Shi B, Ely TD, Howell L, McConathy J, Nemeroff CB.
Abstract : 2beta-Carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (ZIENT) (6) and 2beta-carbomethoxy-3beta-(4'-((E)-2-iodoethenyl)phenyl)nortropane (EIENT) (10) were prepared and evaluated in vitro and in vivo for serotonin transporter (SERT) selectivity and specificity. High specific activity [(123)I]ZIENT and [(123)I]EIENT were synthesized in 45% (n = 5) and 42% (n = 4) radiochemical yield (decay-corrected to end of bombardment (EOB)), respectively, by preparation of the precursor carbomethoxy-3beta-(4'-((Z)-2-trimethylstannylethenyl)phenyl)nortropane (7) and 2beta-carbomethoxy-3beta-(4'-((E)-2-tributylstannylethenyl)phenyl)nortropane (9), respectively, followed by treatment with no carrier-added sodium [(123)I]iodide and hydrogen peroxide in ethanolic HCl. Competition binding in cells stably expressing the transfected human SERT, dopamine transporter (DAT), and norepinephrine transporter (NET) using [(3)H]citalopram, [(3)H]WIN 35,428, and [(3)H]nisoxetine, respectively, demonstrated the following order of SERT affinity (K(i) in nM): ZIENT (0.05) > nor-CIT (0.12) >> EIENT (1.15) > fluvoxamine (1.46). The affinity of ZIENT and EIENT for DAT was 69 and 1.6-fold lower, respectively, than for SERT. In vivo biodistribution and blocking studies were performed in male rats and demonstrated that the brain uptake of [(123)I]ZIENT was selective and specific for SERT-rich regions (hypothalamus, striatum, pons, and prefrontal cortex). SPECT brain imaging studies in monkeys demonstrated high [(123)I]ZIENT uptake in the diencephalon, which resulted in diencephalon-to-cerebellum ratios of 2.12 at 190 min. [(123)I]ZIENT uptake in the diencephalon achieved transient equilibrium at 157 min. In a displacement experiment of [(123)I]ZIENT in a cynomolgus monkey, radioactivity was reduced by 39% in the diencephalon at 101 min following injection of citalopram. The high specific activity one-step radiolabeling preparation and high selectivity of [(123)I]ZIENT for SERT support its candidacy as a radioligand for mapping brain SERT sites.
|
Compound tested for its inhibitory activity against Histamine H1 receptor
|
None
|
0.8
nM
|
|
Journal : J. Med. Chem.
Title : Development of predictive retention-activity relationship models of tricyclic antidepressants by micellar liquid chromatography.
Year : 1999
Volume : 42
Issue : 16
First Page : 3154
Last Page : 3162
Authors : Quiñones-Torrelo C, Sagrado S, Villanueva-Camañas RM, Medina-Hernández MJ.
Abstract : The distribution of tricyclic antidepressants from plasma to brain, where these drugs exert their main clinical action, and other organs is related to transport events across the cell membranes of the different tissues. It could be expected that all the molecular features that condition the transport processes (mainly hydrophobicity and molar total charge) also control the pharmacokinetic and biochemical behavior. Micellar liquid chromatography (MLC) has been proposed to emulate in vitro the partitioning process in the biomembranes. The use of micellar solutions of Brij35 as mobile phases in reversed-phase liquid chromatography has proven to be valid to predict the biological activities of local anesthetics, barbiturates, catecholamines, and benzodiazepines. In this paper, the relationships between the capacity factor in MLC and some pharmacokinetic parameters and biological responses of tricyclic antidepressants are studied. Predictive regression models for the estimation of these parameter values, using the logarithm of the retention data (log k) as independent variable, are also proposed.
|
Inhibition of binding of [3H]imipramine to imipramine receptor in rat brain
|
None
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity.
Year : 1990
Volume : 33
Issue : 10
First Page : 2899
Last Page : 2905
Authors : Yardley JP, Husbands GE, Stack G, Butch J, Bicksler J, Moyer JA, Muth EA, Andree T, Fletcher H, James MN.
Abstract : A series of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives was examined for the ability to inhibit both rat brain imipramine receptor binding and the synaptosomal uptake of norepinephrine (NE) and serotonin (5-HT). Neurotransmitter uptake inhibition was highest for a subset of 2-phenyl-2-(1-hydroxycyclohexyl)dimethylethylamines in which the aryl ring has a halogen or methoxy substituent at the 3- and/or 4-positions. Potential antidepressant activity in this subset was assayed in three rodent models--the antagonism of reserpine-induced hypothermia, the antagonism of histamine-induced ACTH release, and the ability to reduce noradrenergic responsiveness in the rat pineal gland. An acute effect seen in the rat pineal gland with several analogues, including 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol (23) and 1-[2-(dimethylamino)-1)-(4-methoxyphenyl)ethyl]cyclohexanol (4), was taken as a possible correlate of a rapid onset of antidepressant activity. Compound 4 (venlafaxine) is presently undergoing clinical evaluation.
|
In vitro activity for the ability to inhibit the uptake of Norepinephrine into mouse cortical slices.
|
Mus musculus
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Tetracyclic pyridazines as potential psychopharmacological agents.
Year : 1985
Volume : 28
Issue : 7
First Page : 870
Last Page : 875
Authors : Ross BS, Wiley RA.
Abstract : Since the Z isomer of chlorprothixene (1) is far more active than its E counterpart, it was of interest to develop a stereoselective synthesis for this class of compounds. Insertion of a benzenesulfonamido group at the peri position of a chlorprothixene precursor did affect the stereochemistry of side-chain olefin formation, but after hydrolysis attempted removal of the resulting amine led to a Widman-Stoermer cyclization to afford the corresponding tetracyclic pyridazine-containing compound (4). Since this material displayed encouraging activity in neurotransmitter uptake inhibition studies, compounds in which the sulfur bridge was replaced with an ethano bridge similar to that found in imipramine (8) and with sulfur removed (7) were also prepared. These, together with the corresponding peri amino compounds (3, 5, and 6), were tested as neurotransmitter-uptake The two bridged arylamines 3 and 6 displayed potent and selective inhibition of norepinephrine uptake both when tested in vitro and after in vivo administration. The pyridazine-containing compounds exhibited reasonable activity in vitro, but the activity was lost when they were administered in vivo. None of the compounds displayed significant ability to interfere with spiroperidol binding.
|
In vitro inhibition of accumulation of (-)-[3H]Norepinephrine (NA) in mouse brain slices
|
None
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of pyridylallylamines related to zimelidine and their inhibition of neuronal monoamine uptake.
Year : 1981
Volume : 24
Issue : 12
First Page : 1499
Last Page : 1507
Authors : Högberg T, Ulff B, Renyi AL, Ross SB.
Abstract : Analogues of the antidepressant agent zimelidine [6, (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine], a selective inhibitor of neuronal 5-hydroxytryptamine reuptake, were synthesized by several routes with the aim of obtaining compounds having a cis configuration (with respect to pyridyl and allylamine). Two methods utilized suitably substituted benzoylpyridines as starting materials. In two other routes, the bromine in 6 was either directly displaced (CN) or converted via the corresponding lithio derivative to H, Cl, I, Me, SiMe3, and SMe. The configurations were determined by UV, 1H NMR, and lanthanide-induced shifts in 1H NMR. The compounds were evaluated as uptake inhibitors by measuring the accumulation of [3H]noradrenaline and 5-hydroxy[14C]tryptamine in mouse brain slices (in vitro and in vivo). Para substitution favored 5-hydroxytryptamine activity and ortho substitution favored NA activity in the cis series. The in vitro effect on 5-hydroxytryptamine was rather insensitive to variations in the para substituent, whereas pronounced effects in vivo were observed only with Cl, Br (6), and I.
|
Ability to inhibit reuptake of norepinephrine ([3H]NE) at norepinephrine transporter of rat parietal/occipital region
|
None
|
7.36
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of (Z)-9-(heteroarylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes: thiophene analogues as potent norepinephrine transporter inhibitors.
Year : 2003
Volume : 13
Issue : 20
First Page : 3565
Last Page : 3569
Authors : Zhou J, Kläss T, Zhang A, Johnson KM, Wang CZ, Ye Y, Kozikowski AP.
Abstract : To further explore the structure-activity relationships (SARs) of certain tropanes, and to gain insights into the structural features required for high activity and selectivity at norepinephrine transporters (NET), we have introduced both five- and six-membered heteroaromatic moieties such as substituted pyridyl, pyrazinyl, pyrimidyl, thiazolyl, and mono- or disubstituted thienyl groups into conformationally constrained, tricyclic tropane analogues. A number of (Z)-9-(heteroarylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes were synthesized, and their abilities to block dopamine, serotonin, and norepinephrine reuptake by their respective transporters were evaluated. It was found that the five- or six-membered N-containing aromatics are too basic to display high NET activity, while some of the thiophene analogues were identified as potent and selective NET inhibitors.
|
Compound was tested for its inhibitory activity against Noradrenaline receptor
|
Rattus norvegicus
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of predictive retention-activity relationship models of tricyclic antidepressants by micellar liquid chromatography.
Year : 1999
Volume : 42
Issue : 16
First Page : 3154
Last Page : 3162
Authors : Quiñones-Torrelo C, Sagrado S, Villanueva-Camañas RM, Medina-Hernández MJ.
Abstract : The distribution of tricyclic antidepressants from plasma to brain, where these drugs exert their main clinical action, and other organs is related to transport events across the cell membranes of the different tissues. It could be expected that all the molecular features that condition the transport processes (mainly hydrophobicity and molar total charge) also control the pharmacokinetic and biochemical behavior. Micellar liquid chromatography (MLC) has been proposed to emulate in vitro the partitioning process in the biomembranes. The use of micellar solutions of Brij35 as mobile phases in reversed-phase liquid chromatography has proven to be valid to predict the biological activities of local anesthetics, barbiturates, catecholamines, and benzodiazepines. In this paper, the relationships between the capacity factor in MLC and some pharmacokinetic parameters and biological responses of tricyclic antidepressants are studied. Predictive regression models for the estimation of these parameter values, using the logarithm of the retention data (log k) as independent variable, are also proposed.
|
Tested for in vitro reuptake inhibition of [3H]-5-hydroxy tryptamine in pig frontal synaptosomes.
|
Sus scrofa
|
420.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives. Synthesis and antidepressant activity.
Year : 1987
Volume : 30
Issue : 1
First Page : 222
Last Page : 225
Authors : Balsamo A, Giorgi I, Lapucci A, Lucacchini A, Macchia B, Macchia F, Martini C, Rossi A.
Abstract : The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.
|
Tested for in vitro reuptake inhibition of [3H]norepinephrine in pig occipital synaptosomes.
|
Sus scrofa
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives. Synthesis and antidepressant activity.
Year : 1987
Volume : 30
Issue : 1
First Page : 222
Last Page : 225
Authors : Balsamo A, Giorgi I, Lapucci A, Lucacchini A, Macchia B, Macchia F, Martini C, Rossi A.
Abstract : The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.
|
Compound was tested for inhibition of uptake of [14C]5-HT (5-HT) into rat whole brain, in vitro.
|
Rattus norvegicus
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : 2,3,4,4a,5,9b-Hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants.
Year : 1984
Volume : 27
Issue : 4
First Page : 432
Last Page : 439
Authors : Kunstmann R, Lerch U, Gerhards H, Leven M, Schacht U.
Abstract : The synthesis of various diastereoisomeric H4a,H5-cis,H4a,H9b-cis- and H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro -1H-indeno[1,2-b]pyridines is described, as well as the evaluation of their antidepressant potency. Elucidation of structure-activity relationships revealed the H4a,H5-trans compounds as being by far the more active of the two series of diastereoisomers. Pharmacological and biochemical data suggest that these compounds are potential antidepressants with central stimulating properties, which are characterized by strong norepinephrine and dopamine reuptake inhibition.
|
Compound was tested for inhibition of uptake of [14C]norepinephrine (NE) into rat brain hypothalamus, in vitro.
|
Rattus norvegicus
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : 2,3,4,4a,5,9b-Hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants.
Year : 1984
Volume : 27
Issue : 4
First Page : 432
Last Page : 439
Authors : Kunstmann R, Lerch U, Gerhards H, Leven M, Schacht U.
Abstract : The synthesis of various diastereoisomeric H4a,H5-cis,H4a,H9b-cis- and H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro -1H-indeno[1,2-b]pyridines is described, as well as the evaluation of their antidepressant potency. Elucidation of structure-activity relationships revealed the H4a,H5-trans compounds as being by far the more active of the two series of diastereoisomers. Pharmacological and biochemical data suggest that these compounds are potential antidepressants with central stimulating properties, which are characterized by strong norepinephrine and dopamine reuptake inhibition.
|
Inhibition of uptake of tritiated norepinephrine (NE) into rat brain synaptosomes
|
None
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity.
Year : 1990
Volume : 33
Issue : 10
First Page : 2899
Last Page : 2905
Authors : Yardley JP, Husbands GE, Stack G, Butch J, Bicksler J, Moyer JA, Muth EA, Andree T, Fletcher H, James MN.
Abstract : A series of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives was examined for the ability to inhibit both rat brain imipramine receptor binding and the synaptosomal uptake of norepinephrine (NE) and serotonin (5-HT). Neurotransmitter uptake inhibition was highest for a subset of 2-phenyl-2-(1-hydroxycyclohexyl)dimethylethylamines in which the aryl ring has a halogen or methoxy substituent at the 3- and/or 4-positions. Potential antidepressant activity in this subset was assayed in three rodent models--the antagonism of reserpine-induced hypothermia, the antagonism of histamine-induced ACTH release, and the ability to reduce noradrenergic responsiveness in the rat pineal gland. An acute effect seen in the rat pineal gland with several analogues, including 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol (23) and 1-[2-(dimethylamino)-1)-(4-methoxyphenyl)ethyl]cyclohexanol (4), was taken as a possible correlate of a rapid onset of antidepressant activity. Compound 4 (venlafaxine) is presently undergoing clinical evaluation.
|
Ability to inhibit the uptake of norepinephrine (NE) by crude synaptosomes from rat whole brain
|
Rattus norvegicus
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and anxiolytic activity of a series of pyrazino[1,2-a][1,4]benzodiazepine derivatives.
Year : 1980
Volume : 23
Issue : 8
First Page : 952
Last Page : 955
Authors : Smith RG, Lucas RA, Wasley JW.
Abstract : The synthesis and biological evaluation of some derivatives of pyrazino[1,2-a][1,4]benzodiazepines for anxiolytic and antidepressant activity are presented. Significant levels of anxiolytic activity were noted for 7-(o-chlorophenyl)-9-chloro-1,2,3,4,4a,5-hexahydro-3-methylpyrazino[1,2-a];E11,4]benzodiazepine (4b).
|
Compound was tested in vitro for beta -adrenergic sensitivity and administered to rats at 10 mg/kg, perorally, twice daily for 10 days.
|
Rattus norvegicus
|
-50.0
%
|
|
Journal : J. Med. Chem.
Title : (+/-)-4-Aryl-4,5-dihydro-3H-1,3-benzodiazepines. 1. Synthesis and evaluation of (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine and analogues as potential antidepressant agents.
Year : 1982
Volume : 25
Issue : 4
First Page : 340
Last Page : 346
Authors : Geyer HM, Martin LL, Crichlow CA, Dekow FW, Ellis DB, Kruse H, Setescak LL, Worm M.
Abstract : A series of (+/-)-4,5-dihydro-4-phenyl-3H-1,3-benzodiazepines and (+/-)-4,5-dihydro-4-phenyl-1H-1,3-benzodiazepines was synthesized as part of a program to develop novel psychotropics. Of these compounds, (+/-)-4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine (10a, HRP 543) emerged as a potential antidepressant. In in vivo mouse tests (inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity) which are predictive of antidepressant-like activity, 10a is comparable to amitriptyline. The similarity is also maintained in vitro, as both 10a and amitriptyline inhibit norepinephrine and serotonin uptake into rat brain synaptosomes. No significant inhibition of rat brain monoamine oxidase A or B was found with 10a, nor did the compound potentiate tryptamine-induced seizures. On chronic administration, the number of cortical beta-adrenergic receptor sites was similarly reduced by 10a and desipramine. The anticholinergic activity of clinically useful antidepressants, such as amitriptyline, is a proposed cause of side effects which reduce patient compliance. In contrast to the tricyclics, 10a apparently lacks anticholinergic activity, as evidenced in vitro by negligible displacement of [3H]quinuclidinyl benzylate from rat brain muscarinic receptors and in vivo by insignificant antagonism of the cholinergic stimulation produced by physostigmine or oxotremorine. These data suggest that 10a may be clinically useful as a novel nontricyclic antidepressant which is devoid of anticholinergic side-effect liability. Further evaluation of 10a in nonrodent species is in progress.
|
Inhibitory activity of compound against ability of NE to enhance the inhibition produced by GABA after 1 i.p. injection of 10 mg/kg administered (acute treatment)
|
Rattus norvegicus
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : 2,4-Dihydro-3H-1,2,4-triazole-3-thiones as potential antidepressant agents.
Year : 1988
Volume : 31
Issue : 6
First Page : 1253
Last Page : 1258
Authors : Kane JM, Dudley MW, Sorensen SM, Miller FP.
Abstract : A series of 5-aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones was prepared and evaluated for potential antidepressant activity. Members of this series were generally prepared by the alkaline ring closures of the corresponding 1-aroylthiosemicarbazides. Several members of this series were potent antagonists of both RO 4-1284-induced hypothermia and reserpine-induced ptosis in mice. In general the more active members of this series were substituted by haloaryl groups at the 5-position of the triazole nucleus and by methyl groups at the 2- and 4-positions. Exchange of the thiocarbonyl group at the 3-position for a carbonyl group resulted in the complete loss of activity. Biochemical evaluation of the more active members of this series indicated that the aforementioned activities were not a consequence of either norepinephrine (NE) uptake or monoamine oxidase inhibition. In an attempt to determine a mechanism of action, one member of this series, compound 22, was selected for further evaluation in an electrophysiological model where it was found to reduce norepinephrine function in the cerebellum as measured by the NE augmentation of GABA inhibition of Purkinje neurons.
|
Inhibitory activity of compound against ability of NE to enhance the inhibition produced by GABA after ip injection of 10 mg/kg administered once a day for 21 days (chronic treatment)
|
Rattus norvegicus
|
49.0
%
|
|
Journal : J. Med. Chem.
Title : 2,4-Dihydro-3H-1,2,4-triazole-3-thiones as potential antidepressant agents.
Year : 1988
Volume : 31
Issue : 6
First Page : 1253
Last Page : 1258
Authors : Kane JM, Dudley MW, Sorensen SM, Miller FP.
Abstract : A series of 5-aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones was prepared and evaluated for potential antidepressant activity. Members of this series were generally prepared by the alkaline ring closures of the corresponding 1-aroylthiosemicarbazides. Several members of this series were potent antagonists of both RO 4-1284-induced hypothermia and reserpine-induced ptosis in mice. In general the more active members of this series were substituted by haloaryl groups at the 5-position of the triazole nucleus and by methyl groups at the 2- and 4-positions. Exchange of the thiocarbonyl group at the 3-position for a carbonyl group resulted in the complete loss of activity. Biochemical evaluation of the more active members of this series indicated that the aforementioned activities were not a consequence of either norepinephrine (NE) uptake or monoamine oxidase inhibition. In an attempt to determine a mechanism of action, one member of this series, compound 22, was selected for further evaluation in an electrophysiological model where it was found to reduce norepinephrine function in the cerebellum as measured by the NE augmentation of GABA inhibition of Purkinje neurons.
|
Percent inhibitory activity caused by norepinephrine after 1 i.p. injection of 10 mg/kg administered (acute treatment)
|
Rattus norvegicus
|
3.5
%
|
|
Journal : J. Med. Chem.
Title : 2,4-Dihydro-3H-1,2,4-triazole-3-thiones as potential antidepressant agents.
Year : 1988
Volume : 31
Issue : 6
First Page : 1253
Last Page : 1258
Authors : Kane JM, Dudley MW, Sorensen SM, Miller FP.
Abstract : A series of 5-aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones was prepared and evaluated for potential antidepressant activity. Members of this series were generally prepared by the alkaline ring closures of the corresponding 1-aroylthiosemicarbazides. Several members of this series were potent antagonists of both RO 4-1284-induced hypothermia and reserpine-induced ptosis in mice. In general the more active members of this series were substituted by haloaryl groups at the 5-position of the triazole nucleus and by methyl groups at the 2- and 4-positions. Exchange of the thiocarbonyl group at the 3-position for a carbonyl group resulted in the complete loss of activity. Biochemical evaluation of the more active members of this series indicated that the aforementioned activities were not a consequence of either norepinephrine (NE) uptake or monoamine oxidase inhibition. In an attempt to determine a mechanism of action, one member of this series, compound 22, was selected for further evaluation in an electrophysiological model where it was found to reduce norepinephrine function in the cerebellum as measured by the NE augmentation of GABA inhibition of Purkinje neurons.
|
Percent inhibitory activity caused by norepinephrine after ip injection of 10 mg/kg administered once a day for 21 days (chronic treatment)
|
Rattus norvegicus
|
7.8
%
|
|
Journal : J. Med. Chem.
Title : 2,4-Dihydro-3H-1,2,4-triazole-3-thiones as potential antidepressant agents.
Year : 1988
Volume : 31
Issue : 6
First Page : 1253
Last Page : 1258
Authors : Kane JM, Dudley MW, Sorensen SM, Miller FP.
Abstract : A series of 5-aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones was prepared and evaluated for potential antidepressant activity. Members of this series were generally prepared by the alkaline ring closures of the corresponding 1-aroylthiosemicarbazides. Several members of this series were potent antagonists of both RO 4-1284-induced hypothermia and reserpine-induced ptosis in mice. In general the more active members of this series were substituted by haloaryl groups at the 5-position of the triazole nucleus and by methyl groups at the 2- and 4-positions. Exchange of the thiocarbonyl group at the 3-position for a carbonyl group resulted in the complete loss of activity. Biochemical evaluation of the more active members of this series indicated that the aforementioned activities were not a consequence of either norepinephrine (NE) uptake or monoamine oxidase inhibition. In an attempt to determine a mechanism of action, one member of this series, compound 22, was selected for further evaluation in an electrophysiological model where it was found to reduce norepinephrine function in the cerebellum as measured by the NE augmentation of GABA inhibition of Purkinje neurons.
|
Inhibition of uptake of tritiated norepinephrine (NE) in rat synaptosomes
|
None
|
0.65
nM
|
|
Journal : J. Med. Chem.
Title : Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships.
Year : 1987
Volume : 30
Issue : 8
First Page : 1433
Last Page : 1454
Authors : Maryanoff BE, McComsey DF, Gardocki JF, Shank RP, Costanzo MJ, Nortey SO, Schneider CR, Setler PE.
Abstract : A series of pyrrolo[2,1-a]isoquinolines, and related compounds, were examined for antidepressant-like activity, by virtue of their antagonism of tetrabenazine-induced ptosis and sedation, and inhibition of biogenic amine uptake. Thus, we have identified some of the most potent antagonists of TBZ-induced ptosis and some of the most potent inhibitors of the uptake of dopamine, norepinephrine, and serotonin (in rat brain synaptosomes) ever reported. Compounds of particular note, in this regard, are 52b, 29b, 22b, and 48b, respectively. Biological activity was chiefly manifested by the trans isomeric class. Also, through resolution of four compounds, 7b, 24b, 37b, and 48b, biological activity was found to be associated with the (+) enantiomer subgroup (salts measured at 589 nm in MeOH), corresponding to the 6S, 10bR absolute configuration for 7b, 37b, and 48b, and the 6R,10bR configuration for 24b. An X-ray determination on (+)-24b X HBr established its absolute configuration; configurations for the other compounds were verified by enantiospecific synthesis starting with (+)-(R)-2-phenylpyrrolidine. Regarding the pendant phenyl ring, diverse substitution patterns were investigated. Those substitutions that were particularly unfavorable were 3',4',5'-trimethoxy (20b), 2',3',4',5',6'-pentafluoro (34b), 2'-trifluoromethyl (38b), 3',5'-bis(trifluoromethyl) (42b), 4'-n-butyl (44b), 2'-cyano (47b), 4'-methylsulfonyl (50b), and 2'-carboxy (58b). Exceedingly potent compounds, in one way or another, were 10b-12b, 22b, 23b, 25b, 28b, 29b, 33b, 45b, 48b, 51b-53b. The pattern of aromatic substitution had a strong impact on selectivity in the uptake tests (NE vs. DA vs. 5-HT). Activity was significantly diminished by methyl substitution of 7b at the 5 (65, 66), 6 (61b), or 10b (60b) position, by changing the phenyl group of 7b to cyclohexyl (67b), benzyl (68b), or H (72), by moving the phenyl group of 7b to the 5 (69) or 10b (70) position, by expansion of ring B to an azepine (78b), and by modification of ring C to an azetidine (77b), piperidine (75b), or azepine (74b). The interaction of selected analogues with various CNS receptors is reported. Little affinity was shown for the muscarinic cholinergic receptor, suggesting a lack of anticholinergic side effects. Interestingly, 24b and 33b displayed a high affinity for the serotonin-2 receptor, analogous to mianserin and clomipramine. After the body of data was reviewed, derivatives 24b and 48b were chosen for advanced development.
|
Inhibition the uptake of tritiated serotonin (5-HT) by the serotonin transporter SERT in rat synaptosomes
|
None
|
182.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships.
Year : 1987
Volume : 30
Issue : 8
First Page : 1433
Last Page : 1454
Authors : Maryanoff BE, McComsey DF, Gardocki JF, Shank RP, Costanzo MJ, Nortey SO, Schneider CR, Setler PE.
Abstract : A series of pyrrolo[2,1-a]isoquinolines, and related compounds, were examined for antidepressant-like activity, by virtue of their antagonism of tetrabenazine-induced ptosis and sedation, and inhibition of biogenic amine uptake. Thus, we have identified some of the most potent antagonists of TBZ-induced ptosis and some of the most potent inhibitors of the uptake of dopamine, norepinephrine, and serotonin (in rat brain synaptosomes) ever reported. Compounds of particular note, in this regard, are 52b, 29b, 22b, and 48b, respectively. Biological activity was chiefly manifested by the trans isomeric class. Also, through resolution of four compounds, 7b, 24b, 37b, and 48b, biological activity was found to be associated with the (+) enantiomer subgroup (salts measured at 589 nm in MeOH), corresponding to the 6S, 10bR absolute configuration for 7b, 37b, and 48b, and the 6R,10bR configuration for 24b. An X-ray determination on (+)-24b X HBr established its absolute configuration; configurations for the other compounds were verified by enantiospecific synthesis starting with (+)-(R)-2-phenylpyrrolidine. Regarding the pendant phenyl ring, diverse substitution patterns were investigated. Those substitutions that were particularly unfavorable were 3',4',5'-trimethoxy (20b), 2',3',4',5',6'-pentafluoro (34b), 2'-trifluoromethyl (38b), 3',5'-bis(trifluoromethyl) (42b), 4'-n-butyl (44b), 2'-cyano (47b), 4'-methylsulfonyl (50b), and 2'-carboxy (58b). Exceedingly potent compounds, in one way or another, were 10b-12b, 22b, 23b, 25b, 28b, 29b, 33b, 45b, 48b, 51b-53b. The pattern of aromatic substitution had a strong impact on selectivity in the uptake tests (NE vs. DA vs. 5-HT). Activity was significantly diminished by methyl substitution of 7b at the 5 (65, 66), 6 (61b), or 10b (60b) position, by changing the phenyl group of 7b to cyclohexyl (67b), benzyl (68b), or H (72), by moving the phenyl group of 7b to the 5 (69) or 10b (70) position, by expansion of ring B to an azepine (78b), and by modification of ring C to an azetidine (77b), piperidine (75b), or azepine (74b). The interaction of selected analogues with various CNS receptors is reported. Little affinity was shown for the muscarinic cholinergic receptor, suggesting a lack of anticholinergic side effects. Interestingly, 24b and 33b displayed a high affinity for the serotonin-2 receptor, analogous to mianserin and clomipramine. After the body of data was reviewed, derivatives 24b and 48b were chosen for advanced development.
|
Ability to inhibit reuptake of serotonin ([3H]5-HT) at serotonin transporter of rat midbrian
|
None
|
163.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of (Z)-9-(heteroarylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes: thiophene analogues as potent norepinephrine transporter inhibitors.
Year : 2003
Volume : 13
Issue : 20
First Page : 3565
Last Page : 3569
Authors : Zhou J, Kläss T, Zhang A, Johnson KM, Wang CZ, Ye Y, Kozikowski AP.
Abstract : To further explore the structure-activity relationships (SARs) of certain tropanes, and to gain insights into the structural features required for high activity and selectivity at norepinephrine transporters (NET), we have introduced both five- and six-membered heteroaromatic moieties such as substituted pyridyl, pyrazinyl, pyrimidyl, thiazolyl, and mono- or disubstituted thienyl groups into conformationally constrained, tricyclic tropane analogues. A number of (Z)-9-(heteroarylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes were synthesized, and their abilities to block dopamine, serotonin, and norepinephrine reuptake by their respective transporters were evaluated. It was found that the five- or six-membered N-containing aromatics are too basic to display high NET activity, while some of the thiophene analogues were identified as potent and selective NET inhibitors.
|
Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex at 10 uM
|
Cavia porcellus
|
80.3
%
|
|
Journal : J. Med. Chem.
Title : [3H]Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs.
Year : 1985
Volume : 28
Issue : 3
First Page : 381
Last Page : 388
Authors : McNeal ET, Lewandowski GA, Daly JW, Creveling CR.
Abstract : [3H]Batrachotoxinin A benzoate ( [3H]BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of [3H]BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of [3H]BTX-B binding provides a rapid, quantitative, and facile method for the screening and investigation of local anesthetic activity.
|
Inhibitory constant against reuptake of [3H]NE at norepinephrine transporter of rat parietal-occipital cortex
|
Rattus norvegicus
|
7.36
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants.
Year : 2005
Volume : 15
Issue : 10
First Page : 2461
Last Page : 2465
Authors : Zhou J, Kläss T, Johnson KM, Giberson KM, Kozikowski AP.
Abstract : To further explore the structure-activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a-b, 3d, 3f-h, 5b, and 7g were found to be highly potent and selective or mixed norepinephrine transporter (NET) inhibitors with Ki values of 0.8-9.4 nM. Moreover, all of these compounds display weak to extremely weak muscarinic receptor binding affinity, indicating that as potential antidepressants, they may overcome certain side effects that are of concern with other antidepressants, which are thought to be mediated by their anticholinergic properties.
|
Inhibitory constant against reuptake of [3H]5-HT at serotonin transporter of rat midbrain cortex
|
Rattus norvegicus
|
163.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants.
Year : 2005
Volume : 15
Issue : 10
First Page : 2461
Last Page : 2465
Authors : Zhou J, Kläss T, Johnson KM, Giberson KM, Kozikowski AP.
Abstract : To further explore the structure-activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a-b, 3d, 3f-h, 5b, and 7g were found to be highly potent and selective or mixed norepinephrine transporter (NET) inhibitors with Ki values of 0.8-9.4 nM. Moreover, all of these compounds display weak to extremely weak muscarinic receptor binding affinity, indicating that as potential antidepressants, they may overcome certain side effects that are of concern with other antidepressants, which are thought to be mediated by their anticholinergic properties.
|
Binding affinity at NET
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of 11C-labelled (R)-OHDMI and CFMME and their evaluation as candidate radioligands for imaging central norepinephrine transporters with PET.
Year : 2007
Volume : 15
Issue : 2
First Page : 616
Last Page : 625
Authors : Schou M, Pike VW, Sóvágó J, Gulyás B, Gallagher PT, Dobson DR, Walter MW, Rudyk H, Farde L, Halldin C.
Abstract : (R)-1-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-3-methylamino-propan-2-ol ((R)-OHDMI) and (S,S)-1-cyclopentyl-2-(5-fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-ethanol (CFMME) were synthesized and found to be potent inhibitors of norepinephrine reuptake. Each was labelled efficiently in its methyl group with carbon-11 (t(1/2)=20.4 min) as a prospective radioligand for imaging brain norepinephrine transporters (NET) with positron emission tomography (PET). The uptake and distribution of radioactivity in brain following intravenous injection of each radioligand into cynomolgus monkey was examined in vivo with PET. After injection of (R)-[(11)C]OHDMI, the maximal whole brain uptake of radioactivity was very low (1.1% of injected dose; I.D.). For occipital cortex, thalamus, lower brainstem, mesencephalon and cerebellum, radioactivity ratios to striatum at 93 min after radioligand injection were 1.35, 1.35, 1.2, 1.2 and 1.0, respectively. After injection of [(11)C]CFMME, radioactivity readily entered brain (3.5% I.D.). Ratios of radioactivity to cerebellum at 93 min for thalamus, occipital cortex, region of locus coeruleus, mesencephalon and striatum were 1.35, 1.3, 1.3, 1.2 and 1.2, respectively. Radioactive metabolites in plasma were measured by radio-HPLC. (R)-[(11)C]OHDMI represented 75% of plasma radioactivity at 4 min after injection and 6% at 30 min. After injection of [(11)C]CFMME, 84% of the radioactivity in plasma represented parent at 4 min and 20% at 30 min. Since the two new hydroxylated radioligands provide only modest regional differentiation in brain uptake and form potentially troublesome lipophilic radioactive metabolites, they are concluded to be inferior to existing radioligands, such as (S,S)-[(11)C]MeNER, (S,S)-[(18)F]FMeNER-D(2) and (S,S)-[(18)F]FRB-D(4), for the study of brain NETs with PET in vivo.
|
Inhibition of [3H]serotonin uptake in human wild type SERT transfected HEK293 cells
|
Homo sapiens
|
108.0
nM
|
|
Journal : Science
Title : LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.
Year : 2007
Volume : 317
Issue : 5843
First Page : 1390
Last Page : 1393
Authors : Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN.
Abstract : Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.
|
Inhibition of [3H]serotonin uptake in human SERT K490T mutant transfected HEK293 cells
|
Homo sapiens
|
52.4
nM
|
|
Journal : Science
Title : LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.
Year : 2007
Volume : 317
Issue : 5843
First Page : 1390
Last Page : 1393
Authors : Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN.
Abstract : Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.
|
Displacement of [3H]DMI from norepinephrine transporter
|
None
|
580.0
nM
|
|
Journal : J. Nat. Prod.
Title : The role of receptor binding in drug discovery.
Year : 1993
Volume : 56
Issue : 4
First Page : 441
Last Page : 455
Authors : Sweetnam PM, Caldwell L, Lancaster J, Bauer C, McMillan B, Kinnier WJ, Price CH.
Abstract : Radioligand receptor binding has been used extensively to identify and characterize a host of receptors and enzymes targeting virtually every therapeutic area. Many drug discovery programs have been based on the utilization of radioligand receptor binding technology to identify lead compounds which interact with receptors likely to be important in neuronal, immunological, gastrointestinal, and cardiovascular function/dysfunction. There are several obvious advantages to using in vitro receptor binding as a first level screen when compared to in vivo pharmacometric screens. Scientifically, the structure activity data generated in binding assays is a direct reflection of the ligand/receptor interaction minus the complications which result from secondary events, bioavailability, and pharmacodynamic issues. Technically, the binding studies require only a small amount of test compound (< or = 1 mg), while whole animal studies routinely need gram quantities. Similarly, only a small amount of tissue is required, compared with the cost of purchase and maintenance of live animals for in vivo screening. Supply and labor costs are drastically reduced due to the limited volume and test tube based technology of receptor binding. For these reasons receptor binding assays have been utilized with considerable success to discover site specific lead compounds in virtually every therapeutic area.
|
Displacement of [3H]nisoxetine from human norepinephrine transporter expressed in MDCK-Net6 cells
|
Homo sapiens
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors.
Year : 2008
Volume : 51
Issue : 13
First Page : 4038
Last Page : 4049
Authors : Mahaney PE, Gavrin LK, Trybulski EJ, Stack GP, Vu TA, Cohn ST, Ye F, Belardi JK, Santilli AA, Sabatucci JP, Leiter J, Johnston GH, Bray JA, Burroughs KD, Cosmi SA, Leventhal L, Koury EJ, Zhang Y, Mugford CA, Ho DM, Rosenzweig-Lipson SJ, Platt B, Smith VA, Deecher DC.
Abstract : Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.
|
Inhibition of norepinephrine uptake at human norepinephrine transporter expressed in MDCK-Net6 cells
|
Homo sapiens
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors.
Year : 2008
Volume : 51
Issue : 13
First Page : 4038
Last Page : 4049
Authors : Mahaney PE, Gavrin LK, Trybulski EJ, Stack GP, Vu TA, Cohn ST, Ye F, Belardi JK, Santilli AA, Sabatucci JP, Leiter J, Johnston GH, Bray JA, Burroughs KD, Cosmi SA, Leventhal L, Koury EJ, Zhang Y, Mugford CA, Ho DM, Rosenzweig-Lipson SJ, Platt B, Smith VA, Deecher DC.
Abstract : Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.
|
Inhibition of [3H]5HT uptake at human SERT expressed in HEK293 cells
|
Homo sapiens
|
64.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum.
Year : 2007
Volume : 51
Issue : 11
First Page : 4133
Last Page : 4140
Authors : Kelly JX, Smilkstein MJ, Cooper RA, Lane KD, Johnson RA, Janowsky A, Dodean RA, Hinrichs DJ, Winter R, Riscoe M.
Abstract : A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.
|
Inhibition of [3H]norepinephrine uptake at human NET expressed in HEK293 cells
|
Homo sapiens
|
4.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum.
Year : 2007
Volume : 51
Issue : 11
First Page : 4133
Last Page : 4140
Authors : Kelly JX, Smilkstein MJ, Cooper RA, Lane KD, Johnson RA, Janowsky A, Dodean RA, Hinrichs DJ, Winter R, Riscoe M.
Abstract : A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.
|
Inhibition of norepinephrine uptake at human NET expressed in MDCK-Net6 cells
|
Homo sapiens
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual norepinephrine and serotonin reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 9
First Page : 2464
Last Page : 2467
Authors : Vu AT, Cohn ST, Terefenko EA, Moore WJ, Zhang P, Mahaney PE, Trybulski EJ, Goljer I, Dooley R, Bray JA, Johnston GH, Leiter J, Deecher DC.
Abstract : A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
|
Inhibition of [3H]NE uptake at human NET EL2 chimera mutant expressed in african green monkey COS1 cells after 48 hrs
|
Homo sapiens
|
0.7413
nM
|
|
Journal : J. Biol. Chem.
Title : chi-Conotoxin and tricyclic antidepressant interactions at the norepinephrine transporter define a new transporter model.
Year : 2007
Volume : 282
Issue : 24
First Page : 17837
Last Page : 17844
Authors : Paczkowski FA, Sharpe IA, Dutertre S, Lewis RJ.
Abstract : Monoamine neurotransmitter transporters for norepinephrine (NE), dopamine and serotonin are important targets for antidepressants and analgesics. The conopeptide chi-MrIA is a noncompetitive and highly selective inhibitor of the NE transporter (NET) and is being developed as a novel intrathecal analgesic. We used site-directed mutagenesis to generate a suite of mutated transporters to identify two amino acids (Leu(469) and Glu(382)) that affected the affinity of chi-MrIA to inhibit [(3)H]NE uptake through human NET. Residues that increased the K(d) of a tricyclic antidepressant (nisoxetine) were also identified (Phe(207), Ser(225), His(296), Thr(381), and Asp(473)). Phe(207), Ser(225), His(296), and Thr(381) also affected the rate of NE transport without affecting NE K(m). In a new model of NET constructed from the bLeuT crystal structure, chi-MrIA-interacting residues were located at the mouth of the transporter near residues affecting the binding of small molecule inhibitors.
|
Displacement of [125I]RTI-55 from human NET expressed in MDCK cell membrane
|
Homo sapiens
|
0.93
nM
|
|
Journal : J. Nat. Prod.
Title : Antidepressant principles of the roots of Polygala tenuifolia.
Year : 2006
Volume : 69
Issue : 9
First Page : 1305
Last Page : 1309
Authors : Cheng MC, Li CY, Ko HC, Ko FN, Lin YL, Wu TS.
Abstract : [(125)I]RTI-55-membrane binding assay-guided fractionation and separation of a water-soluble extract of the roots of Polygala tenuifolia gave five new oligosaccharide derivatives, polygalatenosides A-E (1-5). The structures of these new oligosaccharides were established on the basis of spectroscopic evidence. Polygalatenosides A and B (1 and 2) showed significant inhibitory activity, with IC(50) values of 30.0 and 6.04 microM, respectively, in this membrane binding assay and acted as norepinephrine reuptake inhibitors through blocking norepinephrine transport.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
84.3
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Inhibition of norepinephrine uptake at human NET expressed in MDCK cells
|
Homo sapiens
|
3.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: a new class of selective norepinephrine reuptake inhibitors.
Year : 2008
Volume : 18
Issue : 18
First Page : 4929
Last Page : 4931
Authors : McComas CC, Vu AT, Mahaney PE, Cohn ST, Fensome A, Marella MA, Nogle L, Trybulski EJ, Ye F, Zhang P, Alfinito P, Bray J, Johnston G, Koury E, Deecher DC.
Abstract : Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
|
Inhibition of norepinephrine uptake at human NET expressed in MDCK-Net6 cells
|
Homo sapiens
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors.
Year : 2008
Volume : 18
Issue : 23
First Page : 6067
Last Page : 6070
Authors : Zhang P, Terefenko EA, McComas CC, Mahaney PE, Vu A, Trybulski E, Koury E, Johnston G, Bray J, Deecher D.
Abstract : A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).
|
Antagonist activity at human 5HT3A receptor expressed in HEK293 cells assessed as inhibition of serotonin-induced inward Na+ current at >= 10 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Molecular properties of psychopharmacological drugs determining non-competitive inhibition of 5-HT3A receptors.
Year : 2009
Volume : 44
Issue : 6
First Page : 2667
Last Page : 2672
Authors : Kornhuber J, Terfloth L, Bleich S, Wiltfang J, Rupprecht R.
Abstract : We developed a structure-property-activity relationship (SPAR)-model for psychopharmacological drugs acting as non-competitive 5-HT(3A) receptor antagonists by using a decision-tree learner provided by the RapidMiner machine learning tool. A single molecular descriptor, namely the molecular dipole moment per molecular weight (mu/MW), predicts whether or not a substance non-competitively antagonizes 5-HT-induced Na(+) currents. A low mu/MW is compatible with drug-cumulation in apolar lipid rafts. This study confirms that size-intensive descriptors allow the development of compact SPAR models.
|
Inhibition of [3H]norepinephrine reuptake at norepinephrine transporter
|
None
|
5.11
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of 1,1-[1-naphthyloxy-2-thiophenyl]-2-methylaminomethylcyclopropanes and their evaluation as inhibitors of serotonin, norepinephrine, and dopamine transporters.
Year : 2009
Volume : 52
Issue : 19
First Page : 5872
Last Page : 5879
Authors : White JD, Juniku R, Huang K, Yang J, Wong DT.
Abstract : Stereodefined trisubstituted cyclopropanes bearing naphthyloxy, thiophenyl, and (N-methylamino)methyl groups were synthesized in enantiopure form employing asymmetric cyclopropanation of (E)- and (Z)-allylic alcohols as the key step. In vitro assays of the synthesized cyclopropanes revealed that the K(i) of one of the enantiomers as a dual inhibitor of serotonin and norepinephrine transporters is in the low nanomolar range and is comparable to that of duloxetine.
|
Inhibition of [3H]norepinephrine uptake at human NET expressed in MDCK-Net6 cells by scintillation counting
|
Homo sapiens
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : 1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: potent, selective, and orally efficacious norepinephrine reuptake inhibitors.
Year : 2009
Volume : 52
Issue : 18
First Page : 5703
Last Page : 5711
Authors : Zhang P, Terefenko EA, Bray J, Deecher D, Fensome A, Harrison J, Kim C, Koury E, Mark L, McComas CC, Mugford CA, Trybulski EJ, Vu AT, Whiteside GT, Mahaney PE.
Abstract : Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.
|
Inhibition of [3H]nisoxetine binding to human NET expressed in MDCK-Net6 cells by plate scintillation counting
|
Homo sapiens
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : 1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: potent, selective, and orally efficacious norepinephrine reuptake inhibitors.
Year : 2009
Volume : 52
Issue : 18
First Page : 5703
Last Page : 5711
Authors : Zhang P, Terefenko EA, Bray J, Deecher D, Fensome A, Harrison J, Kim C, Koury E, Mark L, McComas CC, Mugford CA, Trybulski EJ, Vu AT, Whiteside GT, Mahaney PE.
Abstract : Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.
|
Inhibition of human NET expressed in MDCK-Net6 cells
|
Homo sapiens
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-activity relationships of the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ol series of monoamine reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 19
First Page : 5807
Last Page : 5810
Authors : Mahaney PE, Kim CY, Coghlan RD, Cohn ST, Heffernan GD, Huselton CA, Terefenko EA, Vu AT, Zhang P, Burroughs KD, Cosmi SA, Bray JA, Johnston GH, Deecher DC, Trybulski EJ.
Abstract : The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.
|
Inhibition of norepinephrine reuptake at human NET expressed in MDCK-Net6 cells
|
Homo sapiens
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols.
Year : 2009
Volume : 19
Issue : 17
First Page : 5029
Last Page : 5032
Authors : Kim CY, Mahaney PE, McConnell O, Zhang Y, Manas E, Ho DM, Deecher DC, Trybulski EJ.
Abstract : A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC(50)=28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.
|
Inhibition of norepinephrine reuptake at NET
|
None
|
0.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Dual acting norepinephrine reuptake inhibitors and 5-HT(2A) receptor antagonists: Identification, synthesis and activity of novel 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles.
Year : 2009
Volume : 17
Issue : 22
First Page : 7802
Last Page : 7815
Authors : Heffernan GD, Coghlan RD, Manas ES, McDevitt RE, Li Y, Mahaney PE, Robichaud AJ, Huselton C, Alfinito P, Bray JA, Cosmi SA, Johnston GH, Kenney T, Koury E, Winneker RC, Deecher DC, Trybulski EJ.
Abstract : The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.
|
Inhibition of norepinephrine uptake at human NET expressed in MDCK-Net6 cells
|
Homo sapiens
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : 1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as potent and selective norepinephrine reuptake inhibitors.
Year : 2010
Volume : 53
Issue : 5
First Page : 2051
Last Page : 2062
Authors : Vu AT, Cohn ST, Zhang P, Kim CY, Mahaney PE, Bray JA, Johnston GH, Koury EJ, Cosmi SA, Deecher DC, Smith VA, Harrison JE, Leventhal L, Whiteside GT, Kennedy JD, Trybulski EJ.
Abstract : Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.
|
Displacement of [3H]nisoxetine from human NET expressed in MDCK-Net6 cells
|
Homo sapiens
|
3.3
nM
|
|
Journal : J. Med. Chem.
Title : 1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as potent and selective norepinephrine reuptake inhibitors.
Year : 2010
Volume : 53
Issue : 5
First Page : 2051
Last Page : 2062
Authors : Vu AT, Cohn ST, Zhang P, Kim CY, Mahaney PE, Bray JA, Johnston GH, Koury EJ, Cosmi SA, Deecher DC, Smith VA, Harrison JE, Leventhal L, Whiteside GT, Kennedy JD, Trybulski EJ.
Abstract : Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.
|
Inhibition of human NET transfected in MDCK-Net6 cells
|
Homo sapiens
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Heterocyclic cycloalkanol ethylamines as norepinephrine reuptake inhibitors.
Year : 2010
Volume : 20
Issue : 9
First Page : 2809
Last Page : 2812
Authors : Sabatucci JP, Mahaney PE, Leiter J, Johnston G, Burroughs K, Cosmi S, Zhang Y, Ho D, Deecher DC, Trybulski E.
Abstract : A series of heterocyclic cycloalkanol ethylamines have been prepared to expand our norepinephrine reuptake inhibitor (NRI) program. Synthesis of a variety of heterocycles identified (+)-S-21, a potent NRI efficacious in an animal model for thermoregulatory dysfunction.
|
Inhibition of human NET-mediated norepinephrine uptake in MDCK-Net6 cells
|
Homo sapiens
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231).
Year : 2010
Volume : 53
Issue : 11
First Page : 4511
Last Page : 4521
Authors : O'Neill DJ, Adedoyin A, Alfinito PD, Bray JA, Cosmi S, Deecher DC, Fensome A, Harrison J, Leventhal L, Mann C, McComas CC, Sullivan NR, Spangler TB, Uveges AJ, Trybulski EJ, Whiteside GT, Zhang P.
Abstract : Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.
|
Displacement of [3H]nisoxetine from human NET expressed in MDCK-Net6 cells
|
Homo sapiens
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231).
Year : 2010
Volume : 53
Issue : 11
First Page : 4511
Last Page : 4521
Authors : O'Neill DJ, Adedoyin A, Alfinito PD, Bray JA, Cosmi S, Deecher DC, Fensome A, Harrison J, Leventhal L, Mann C, McComas CC, Sullivan NR, Spangler TB, Uveges AJ, Trybulski EJ, Whiteside GT, Zhang P.
Abstract : Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.
|
Displacement of [3H]nisoxetine from rat NET in rat cerebral cortex
|
Rattus norvegicus
|
0.78
nM
|
|
Journal : J. Med. Chem.
Title : Diaryldiamines with dual inhibition of the histamine H(3) receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain.
Year : 2010
Volume : 53
Issue : 21
First Page : 7869
Last Page : 7873
Authors : Altenbach RJ, Black LA, Strakhova MI, Manelli AM, Carr TL, Marsh KC, Wetter JM, Wensink EJ, Hsieh GC, Honore P, Garrison TR, Brioni JD, Cowart MD.
Abstract : A series of compounds was designed as dual inhibitors of the H(3) receptor and the norepinephrine transporter. Compound 5 (rNET K(i) = 14 nM; rH(3)R K(i) = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain.
|
Inhibition of human NET
|
Homo sapiens
|
0.83
nM
|
|
Journal : J. Med. Chem.
Title : Diaryldiamines with dual inhibition of the histamine H(3) receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain.
Year : 2010
Volume : 53
Issue : 21
First Page : 7869
Last Page : 7873
Authors : Altenbach RJ, Black LA, Strakhova MI, Manelli AM, Carr TL, Marsh KC, Wetter JM, Wensink EJ, Hsieh GC, Honore P, Garrison TR, Brioni JD, Cowart MD.
Abstract : A series of compounds was designed as dual inhibitors of the H(3) receptor and the norepinephrine transporter. Compound 5 (rNET K(i) = 14 nM; rH(3)R K(i) = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain.
|
Inhibition of SERT
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Diaryldiamines with dual inhibition of the histamine H(3) receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain.
Year : 2010
Volume : 53
Issue : 21
First Page : 7869
Last Page : 7873
Authors : Altenbach RJ, Black LA, Strakhova MI, Manelli AM, Carr TL, Marsh KC, Wetter JM, Wensink EJ, Hsieh GC, Honore P, Garrison TR, Brioni JD, Cowart MD.
Abstract : A series of compounds was designed as dual inhibitors of the H(3) receptor and the norepinephrine transporter. Compound 5 (rNET K(i) = 14 nM; rH(3)R K(i) = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain.
|
Inhibition of human NET expressed in MDCK-Net6 cells assessed as inhibition of norepinephrine uptake
|
Homo sapiens
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel selective norepinephrine inhibitors: 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (WYE-114152).
Year : 2011
Volume : 54
Issue : 19
First Page : 6824
Last Page : 6831
Authors : O'Neill DJ, Adedoyin A, Bray JA, Deecher DC, Fensome A, Goldberg JA, Harrison J, Leventhal L, Mann C, Mark L, Nogle L, Sullivan NR, Spangler TB, Terefenko EA, Trybulski EJ, Uveges AJ, Vu A, Whiteside GT, Zhang P.
Abstract : Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.
|
Displacement of [3H]nisoxetine from human NET expressed in MDCK-Net6 cells
|
Homo sapiens
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel selective norepinephrine inhibitors: 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (WYE-114152).
Year : 2011
Volume : 54
Issue : 19
First Page : 6824
Last Page : 6831
Authors : O'Neill DJ, Adedoyin A, Bray JA, Deecher DC, Fensome A, Goldberg JA, Harrison J, Leventhal L, Mann C, Mark L, Nogle L, Sullivan NR, Spangler TB, Terefenko EA, Trybulski EJ, Uveges AJ, Vu A, Whiteside GT, Zhang P.
Abstract : Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.
|
TP_TRANSPORTER: increase in Calcein-AM intracellular accumulation (Calcein-AM: ? uM, Desipramine: 100 uM) in MDR1-expressing MDCKII cells
|
None
|
12.8
%
|
|
Journal : J. Pharmacol. Exp. Ther.
Title : Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs.
Year : 2002
Volume : 303
Issue : 1
First Page : 1029
Last Page : 1037
Authors : Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW.
Abstract : Membrane permeability and P-glycoprotein (Pgp) can be limiting factors for blood-brain barrier penetration. The objectives of this study were to determine whether there are differences in the in vitro permeability, Pgp substrate profiles, and physicochemical properties of drugs for central nervous system (CNS) and non-CNS indications, and whether these differences are useful criteria in selecting compounds for drug development. Apparent permeability (P(app)) and Pgp substrate profiles for 93 CNS (n = 48) and non-CNS (n = 45) drugs were determined by monolayer efflux. Calcein-AM inhibition assays were used to supplement the efflux results. The CNS set (2 of 48, 4.2%) had a 7-fold lower incidence of passive permeability values <150 nm/s compared with the non-CNS set (13 of 45, 28.9%). The majority of drugs (72.0%, 67 of 93) were not Pgp substrates; however, 49.5% (46 of 93) were positive in the calcein-AM assay when tested at 100 microM. The CNS drug set (n = 7 of 48, 14.6%) had a 3-fold lower incidence of Pgp-mediated efflux than the non-CNS drug set (n = 19 of 45, 42.2%). Analysis of 18 physicochemical properties revealed that the CNS drug set had fewer hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surface area, and reduced flexibility compared with the non-CNS group (p < 0.05), properties that enhance membrane permeability. This study on a large, diverse set of marketed compounds clearly demonstrates that permeability, Pgp-mediated efflux, and certain physicochemical properties are factors that differentiate CNS and non-CNS drugs. For CNS delivery, a drug should ideally have an in vitro passive permeability >150 nm/s and not be a good (B --> A/A --> B ratio <2.5) Pgp substrate.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
25.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
3.2
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-4.4
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human SERT expressed in HEK293-MSR cells by 5-HT uptake assay
|
Homo sapiens
|
560.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Basic N-interlinked imipramines show apoptotic activity against malignant cells including Burkitt's lymphoma.
Year : 2013
Volume : 23
Issue : 5
First Page : 1220
Last Page : 1224
Authors : Bright SA, Brinkø A, Larsen MT, Sinning S, Williams DC, Jensen HH.
Abstract : We here report the synthesis of ethylene glycol N-interlinked imipramine dimers of various lengths from the tricyclic antidepressant desipramine via an amide coupling reaction followed by reduction with lithium aluminium hydride. The target molecules were found to be potent inhibitors of cellular viability while inducing cell type specific death mechanisms in three cancer cell lines including a highly chemoresistant Burkitt's lymphoma cell line. Basic amine analogues were found to be important for increased potency. Imipramine and desipramine were also tested for apoptotic activity and were found to be much less active than the novel dimeric compounds. Imipramine dimers were only found to be moderate inhibitors of the human serotonin transporter (hSERT) having IC(50) values in the micromolar region whilst the induction of cell death occurred independently of hSERT expression. These results demonstrate the potential of newly designed and synthesised imipramines derivatives for use against malignant cells, including those resistant to standard chemotherapy.
|
Displacement of [125I]RTI55 from human recombinant norepinephrine transporter expressed in MDCK cells after 3 hrs
|
Homo sapiens
|
0.92
nM
|
|
Displacement of [125I]RTI55 from human recombinant norepinephrine transporter expressed in MDCK cells after 3 hrs
|
Homo sapiens
|
0.93
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [125I]RTI55 from human recombinant norepinephrine transporter expressed in MDCK cells at 10 uM after 3 hrs relative to control
|
Homo sapiens
|
49.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [3H]Nisoxetine from human recombinant NET over-expressed in dog MDCK cells
|
Homo sapiens
|
1.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel 3,4-diaryl lactam derivatives as triple reuptake inhibitors.
Year : 2013
Volume : 23
Issue : 20
First Page : 5515
Last Page : 5518
Authors : Park JE, Song C, Choi K, Sim T, Moon B, Roh EJ.
Abstract : A series of 3,4-diarylpyrrolidin-2-one was designed, prepared and evaluated as triple reuptake inhibitors for antidepressant. Most compounds exhibited comparable in vitro efficacy as norepinephrine and dopamine transporter reuptake inhibitors. Especially, 2i showed better potency than GBR-12909 (IC50=14 nM) which was used as reference compound for dopamine transporter. In addition, 2a and 2b showed inhibition (5.17 μM-85.6 nM) for three transporters.
|
Displacement of [3H]Nisoxetine from norepinephrine transporter (unknown origin)
|
Homo sapiens
|
1.148
nM
|
|
Displacement of [3H]Nisoxetine from norepinephrine transporter (unknown origin)
|
Homo sapiens
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and comparative receptor binding affinities of novel, isomeric pyridoindolobenzazepine scaffolds.
Year : 2014
Volume : 24
Issue : 2
First Page : 576
Last Page : 579
Authors : Rajagopalan R, Bandyopadhyaya A, Rajagopalan DR, Rajagopalan P.
Abstract : Compounds 7, 8, and 9, derived from the novel scaffolds 3, 5, and 6, were synthesized and evaluated in vitro. The b,c→c,d shift of the E-phenyl ring resulted in a large decrease (ca. 20- to 1000-fold) in binding to the 5-HT2A, 5-HT2C and H2, receptors, and a modest decrease (ca. 10- to 20-fold) in binding to the 5-HT5A, D2, D5, and α1D, receptors. The b,c→d,e shift resulted in a large decrease in binding to the 5-HT1D, 5-HT2C, 5-HT6, and H1 receptors, a modest decrease in binding to 5-HT1A, 5-HT5A and D2, D5, α2B, and H2 receptors, and a large increase in affinity to the 5-HT3, 5-HT6, and σ1 receptors.
|
Antidepressant activity in ip dosed NMRI albino mouse assessed as inhibition of [3H]5-HT accumulation in hypothalamus after 0.5 hrs
|
Mus musculus
|
23.0
%
|
|
Journal : J. Med. Chem.
Title : Antidepressant agents. 9. 3,3-Diphenylcyclobutylamines, a new class of central stimulants.
Year : 1978
Volume : 21
Issue : 1
First Page : 78
Last Page : 82
Authors : Carnmalm B, Rämsby S, Renyi AL, Ross SB, Ogren SO.
Abstract : 3,3-Diphenylcyclobutylamine (4), N-methyl-3,3-diphenylcyclobutylamine (6), and N,N-dimethyl-3,3-diphenyl-cyclobutylamine (7) have been prepared and tested as potential antidepressant agents. The secondary (6) and tertiary (7) amines strongly decrease the accumulation of NA and 5-HT in brain slices in vitro and in vivo. The cyclobutylamines also cause motor stimulation. The most potent compound in this respect is the tertiary amine 7. The increase in locomotion is not blocked by pretreatment with phenoxybenzamine, methergoline, or alpha-methyltyrosine. Pretreatment with pimozide or reserpine reduces the hyperactivity induced by 7. This hyperstimulation seems to be caused by a mechanism of action which differs from that of amphetamine. 7 may cause increase in locomotion by release of dopamine from granular stores.
|
Antidepressant activity in ip dosed NMRI albino mouse assessed as inhibition of [3H]DA accumulation in hypothalamus after 0.5 hrs
|
Mus musculus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Antidepressant agents. 9. 3,3-Diphenylcyclobutylamines, a new class of central stimulants.
Year : 1978
Volume : 21
Issue : 1
First Page : 78
Last Page : 82
Authors : Carnmalm B, Rämsby S, Renyi AL, Ross SB, Ogren SO.
Abstract : 3,3-Diphenylcyclobutylamine (4), N-methyl-3,3-diphenylcyclobutylamine (6), and N,N-dimethyl-3,3-diphenyl-cyclobutylamine (7) have been prepared and tested as potential antidepressant agents. The secondary (6) and tertiary (7) amines strongly decrease the accumulation of NA and 5-HT in brain slices in vitro and in vivo. The cyclobutylamines also cause motor stimulation. The most potent compound in this respect is the tertiary amine 7. The increase in locomotion is not blocked by pretreatment with phenoxybenzamine, methergoline, or alpha-methyltyrosine. Pretreatment with pimozide or reserpine reduces the hyperactivity induced by 7. This hyperstimulation seems to be caused by a mechanism of action which differs from that of amphetamine. 7 may cause increase in locomotion by release of dopamine from granular stores.
|
Displacement of [3H]nisoxetine from human NET expressed in HEK293 cells measured after 30 mins
|
Homo sapiens
|
2.5
nM
|
|
Journal : J Med Chem
Title : Development of Novel Alkoxyisoxazoles as Sigma-1 Receptor Antagonists with Antinociceptive Efficacy.
Year : 2016
Volume : 59
Issue : 13
First Page : 6329
Last Page : 6343
Authors : Sun H, Shi M, Zhang W, Zheng YM, Xu YZ, Shi JJ, Liu T, Gunosewoyo H, Pang T, Gao ZB, Yang F, Tang J, Yu LF.
Abstract : A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.
|
Displacement of [3H]nisoxetine from human NET expressed in HEK293 cells at 10 uM measured after 30 mins
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Development of Novel Alkoxyisoxazoles as Sigma-1 Receptor Antagonists with Antinociceptive Efficacy.
Year : 2016
Volume : 59
Issue : 13
First Page : 6329
Last Page : 6343
Authors : Sun H, Shi M, Zhang W, Zheng YM, Xu YZ, Shi JJ, Liu T, Gunosewoyo H, Pang T, Gao ZB, Yang F, Tang J, Yu LF.
Abstract : A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
16.09
%
|
|
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
|
0.02
%
|
|
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
|
0.02
%
|
|
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.
|
Inhibition of norepinephrine transporter (unknown origin)
|
Homo sapiens
|
3.917
nM
|
|
|
Displacement of [3H]-Nisoxetine from human NET expressed in HEK cell membrane assessed as inhibition constant by radioligand binding assay
|
Homo sapiens
|
3.0
nM
|
|
|
Displacement of [3H]-Nisoxetine from human NET expressed in HEK cell membrane at 10 uM by radioligand binding assay relative to control
|
Homo sapiens
|
50.0
%
|
|
