|
Binding affinity towards 5-hydroxytryptamine 2 receptor
|
None
|
23.0
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.
|
Binding affinity towards 5-hydroxytryptamine 2A receptor using [3H]ketanserin
|
None
|
94.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural determinants for high 5-HT(2A) receptor affinity of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (SpAMDA).
Year : 2004
Volume : 14
Issue : 9
First Page : 2279
Last Page : 2283
Authors : Peddi S, Roth BL, Glennon RA, Westkaemper RB.
Abstract : The synthesis and 5-HT(2A) receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (4), a structurally unique tetracyclic 5-HT(2A) receptor antagonist, are described. The characteristics of the parent compound prove to be necessary for optimal 5-HT(2A) receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce compounds with reasonably high 5-HT(2A) receptor affinities. In addition, the parent compound is shown to have high 5-HT(2) receptor selectivity.
|
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.
|
Binding affinity to 5-hydroxytryptamine 2C receptor using [3H]Mesulergine as radioligand in stably transfected 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.
|
Binding affinity towards 5-hydroxytryptamine 2C receptor using [3H]mesulergine as radioligand
|
None
|
160.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural determinants for high 5-HT(2A) receptor affinity of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (SpAMDA).
Year : 2004
Volume : 14
Issue : 9
First Page : 2279
Last Page : 2283
Authors : Peddi S, Roth BL, Glennon RA, Westkaemper RB.
Abstract : The synthesis and 5-HT(2A) receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (4), a structurally unique tetracyclic 5-HT(2A) receptor antagonist, are described. The characteristics of the parent compound prove to be necessary for optimal 5-HT(2A) receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce compounds with reasonably high 5-HT(2A) receptor affinities. In addition, the parent compound is shown to have high 5-HT(2) receptor selectivity.
|
Compound was tested for its inhibitory activity against 5-hydroxytryptamine receptor
|
Rattus norvegicus
|
44.0
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
|
160.0
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
|
160.0
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.
|
In vitro binding affinity at Alpha-1 adrenergic receptor by radioligand binding assay using [3H]prazosin
|
None
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological characterization of ABT-200: a putative novel antidepressant combining potent -2 antagonism with moderate NE uptake inhibition
Year : 1994
Volume : 4
Issue : 11
First Page : 1319
Last Page : 1322
Authors : Zelle RE, Hancock AA, Buckner SA, Basha FZ, Tietje K, DeBernardis JF, Meyer MD
|
Concentration of compound for 50% displacement of [3H]WB-4101 from Alpha-1 adrenergic receptor of rat brain
|
None
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogues.
Year : 1980
Volume : 23
Issue : 8
First Page : 865
Last Page : 873
Authors : Martin AR, Paradkar VM, Peng GW, Speth RC, Yamamura HI, Horn AS.
|
In vitro binding affinity at Alpha-2 adrenergic receptor in rat cortex by radioligand binding assay using [3H]rauwolscine
|
None
|
255.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological characterization of ABT-200: a putative novel antidepressant combining potent -2 antagonism with moderate NE uptake inhibition
Year : 1994
Volume : 4
Issue : 11
First Page : 1319
Last Page : 1322
Authors : Zelle RE, Hancock AA, Buckner SA, Basha FZ, Tietje K, DeBernardis JF, Meyer MD
|
Binding affinity to Dopamine receptor D2 using [3H]spiperone as radioligand in stably transfected NIH3T3 cells
|
None
|
726.0
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.
|
Concentration of compound for 50% displacement of [3H]spiperone from Dopamine receptor in rat brain
|
None
|
645.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogues.
Year : 1980
Volume : 23
Issue : 8
First Page : 865
Last Page : 873
Authors : Martin AR, Paradkar VM, Peng GW, Speth RC, Yamamura HI, Horn AS.
|
Binding affinity towards dopamine receptor D2 using [3H]spiperone as radioligand
|
None
|
726.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural determinants for high 5-HT(2A) receptor affinity of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (SpAMDA).
Year : 2004
Volume : 14
Issue : 9
First Page : 2279
Last Page : 2283
Authors : Peddi S, Roth BL, Glennon RA, Westkaemper RB.
Abstract : The synthesis and 5-HT(2A) receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (4), a structurally unique tetracyclic 5-HT(2A) receptor antagonist, are described. The characteristics of the parent compound prove to be necessary for optimal 5-HT(2A) receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce compounds with reasonably high 5-HT(2A) receptor affinities. In addition, the parent compound is shown to have high 5-HT(2) receptor selectivity.
|
Binding affinity towards dopamine receptor D2 at 1.0 uM concentration
|
None
|
63.0
%
|
|
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.
|
Concentration required to reducing the histamine induced contraction by 50% was measured
|
Cavia porcellus
|
0.032
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antidepressant activity of substituted (omega-aminoalkoxy)benzene derivatives.
Year : 1981
Volume : 24
Issue : 2
First Page : 145
Last Page : 148
Authors : Kikumoto R, Tobe A, Tonomura S.
Abstract : A series of substituted (omega-aminoalkoxy)benzene derivatives has been synthesized and screened for potential antidepressant activities. The effect of structural variation of these molecules has been systematically examined. Antidepressant activity was clearly displayed by 2-benzyl-1-[4-(methylamino)butoxy]benzene (7), 2-(2-hydroxybenzyl)-1-[4-(methylamino)butoxy]benzene (19), 1-[4-(methylamino)butoxy]-2-phenoxybenzene (29), and 1-[4-(methylamino)butoxy]-2-(phenylthio)benzene (31) in further pharmacological studies. These compounds did not possess the anticholinergic, antihistaminic, and muscle-relaxant side effects common to tricyclic antidepressants.
|
Compound tested for its inhibitory activity against Histamine H1 receptor
|
None
|
0.06
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.
|
Binding affinity towards histamine receptor by inhibiting specific binding of [3H]-mepyramine (3 nM) in vitro to membranes of rat brain without cerebellum
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : cis-1,3,4,6,7,11b-Hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a] isoquinoline: a new atypical antidepressant.
Year : 1984
Volume : 27
Issue : 8
First Page : 995
Last Page : 1003
Authors : Griffith RC, Gentile RJ, Robichaud RC, Frankenheim J.
Abstract : Molecular modelling studies suggested the synthesis of cis-1,3,4,6,7, 11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (7a) as a rigid analogue of the atypical antidepressant mianserin. Acylation of 2,2-diphenylethylamine with chloroacetyl chloride gives the chloroacetamide (2). Cyclization of 2 with P2O5 in xylene provides 1-(chloromethyl)-3,4-dihydro-4-phenylisoquinoline (3). Amination of 3, followed by reduction, gives the isomeric (aminomethyl)tetrahydroisoquinolines (4a and 5). Treatment of 4a with diethyl oxalate, followed by reduction of the diamide with borane, provides 7a. A variety of N-substituted, aromatic substituted, and optically resolved derivatives were prepared and evaluated for anticholinergic, antihistaminic, and antidepressant activity. In particular, the target cis isomer 7a as predicted from the modelling studies appears to possess excellent atypical antidepressant activity. This activity resides in the (+)-S,S optical isomer 10, which has the same absolute configuration as (+)-mianserin.
|
Inhibition of binding of [3H]imipramine to imipramine receptor in rat brain
|
None
|
1.7
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.
|
Binding affinity against imipramine receptor was determined in homogenized rat cortex tissue using [3H]-imipramine as radioligand
|
Rattus norvegicus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic compounds as selective antimuscarinics. 1. Structural requirements for selectivity toward the muscarinic acetylcholine receptor in a series of pirenzepine and imipramine analogues.
Year : 1987
Volume : 30
Issue : 8
First Page : 1378
Last Page : 1382
Authors : Eberlein WG, Trummlitz G, Engel WW, Schmidt G, Pelzer H, Mayer N.
Abstract : The M1-selective antiulcer drug pirenzepine (1) is a tricyclic compound with close resemblance to tricyclic psychotropic agents such as imipramine (2). Despite this fact, pirenzepine is devoid of any psychotropic effects, exhibiting measurable antagonistic effects in biochemical assays and receptor binding studies only toward the muscarinic receptor system. To understand how different groups in these tricyclic molecules affect binding affinities, a set of nine compounds structurally related to pirenzepine (1) and imipramine (2) has been selected for analysis, comprising three different tricycles and three different side chains. The compounds were tested for their affinity to the imipramine and muscarinic receptors in homogenized rat cortex tissue. The result of these studies suggests that it is the nature and placement of accessory groups that determine the differences in receptor recognition and the binding process. In the case of pirenzepine (1), preferential binding toward the muscarinic receptor is brought about by the endocyclic amide group, by the positioning of the protonated N atom of the side chain, and to a minor extent by the exocyclic amide group. From these findings a putative model for the explanation of selective binding of pirenzepine (1) to the muscarinic receptor has been derived.
|
Compound at an intraperitoneal dose of 10 mg/Kg was tested for the inhibition of abdominal constriction in mice
|
Mus musculus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrrolobenzodiazepines and related systems. 2. Synthesis and biological properties of isonoraptazepine derivatives.
Year : 1992
Volume : 35
Issue : 24
First Page : 4533
Last Page : 4541
Authors : Massa S, Artico M, Mai A, Corelli F, Botta M, Tafi A, Pantaleoni GC, Giorgi R, Coppolino MF, Cagnotto A.
Abstract : The synthesis of some derivatives and analogues of 12,13,14,14a-tetrahydro-9H,11H-pyrazino-[2,1-c]pyrrolo[1,2- a][1,4]benzodiazepine (isonoraptazepine) is reported. The new derivatives have been subjected to pharmacological tests for evaluation of antidepressant effects. Neurobehavioral assays were also carried out to acquire data on neurotoxicity and sedative action. Isonoraptazepine analogues and derivatives lacked the pharmacological activity of mianserin and aptazepine and showed properties similar to imipramine. Molecular modeling studies revealed structural similarities between isonoraptazepine derivatives and imipramine, thus explaining the similar pharmacological profile found in some of the tests employed. Based on pharmacological data the title compounds cannot be regarded as alpha 2 presynaptic adrenoceptors antagonists. In vitro studies for receptor binding gave support to this observation. The above studies lead us to conclude that isonoraptazepine derivatives are conformationally restricted analogues of imipramine, but their antidepressant activity cannot be correlated to inhibition of 5HT uptake. Among the derivatives tested, 7b and 8e show some affinity for the d-fenfluramine receptor site, a serotonin presynaptic site connected with anorectic activity.
|
In vitro activity for the ability to inhibit the uptake of Serotonin into mouse cortical slices.
|
Mus musculus
|
300.0
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 [14C]5-HT (5-HT) in mouse brain slices
|
None
|
300.0
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.
|
Tested in vitro for norepinephrine (NE) neuronal uptake inhibition
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrroloisoquinoline antidepressants. 3. A focus on serotonin.
Year : 1990
Volume : 33
Issue : 10
First Page : 2793
Last Page : 2797
Authors : Maryanoff BE, Vaught JL, Shank RP, McComsey DF, Costanzo MJ, Nortey SO.
Abstract : A collection of hexahydropyrroloisoquinoline derivatives (1-22), which represent a class of compounds that inhibit the neuronal uptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT), was investigated in vivo for serotonin-potentiating properties in the mouse head-twitch and rat serotonin syndrome assays. The p-methylthio compound 3b (McN-5652-Z) was found to possess exceptional activity in these assays, and the activity was attributable almost exclusively to the (+)-6S,10bR enantiomer. Ten closely related analogues were synthesized, tested, and compared among themselves and with some previously prepared compounds, both in vivo and in vitro. Several trans diastereomers exhibited strong inhibition of 5-HT uptake and substantial potentiation of 5-HT, while the cis diastereomers (3a, 4a, and 10a) tested were virtually devoid of such activity. Although 3b was only moderately selective in inhibiting the uptake of 5-HT vs NE, its 10-substituted analogues 4b, 7b-9b had improved 5-HT selectivity relative to NE, to the extent of 20-25 times (150-200 times relative to DA). Of these more selective compounds (in vitro), only 4b and 7b had substantial activity in vivo. Sulfoxide 11b appeared to function as a prodrug of 3b in vivo.
|
Tested in vitro for serotonin(5-HT) neuronal uptake inhibition
|
None
|
42.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrroloisoquinoline antidepressants. 3. A focus on serotonin.
Year : 1990
Volume : 33
Issue : 10
First Page : 2793
Last Page : 2797
Authors : Maryanoff BE, Vaught JL, Shank RP, McComsey DF, Costanzo MJ, Nortey SO.
Abstract : A collection of hexahydropyrroloisoquinoline derivatives (1-22), which represent a class of compounds that inhibit the neuronal uptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT), was investigated in vivo for serotonin-potentiating properties in the mouse head-twitch and rat serotonin syndrome assays. The p-methylthio compound 3b (McN-5652-Z) was found to possess exceptional activity in these assays, and the activity was attributable almost exclusively to the (+)-6S,10bR enantiomer. Ten closely related analogues were synthesized, tested, and compared among themselves and with some previously prepared compounds, both in vivo and in vitro. Several trans diastereomers exhibited strong inhibition of 5-HT uptake and substantial potentiation of 5-HT, while the cis diastereomers (3a, 4a, and 10a) tested were virtually devoid of such activity. Although 3b was only moderately selective in inhibiting the uptake of 5-HT vs NE, its 10-substituted analogues 4b, 7b-9b had improved 5-HT selectivity relative to NE, to the extent of 20-25 times (150-200 times relative to DA). Of these more selective compounds (in vitro), only 4b and 7b had substantial activity in vivo. Sulfoxide 11b appeared to function as a prodrug of 3b in vivo.
|
Concentration of compound for 50% displacement of [3H]QNB from Muscarinic acetylcholine receptor in rat brain
|
None
|
269.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogues.
Year : 1980
Volume : 23
Issue : 8
First Page : 865
Last Page : 873
Authors : Martin AR, Paradkar VM, Peng GW, Speth RC, Yamamura HI, Horn AS.
|
Binding affinity against Muscarinic acetylcholine receptor was determined in homogenized rat cortex tissue using [3H]N-methylscopolamine as radioligand
|
None
|
65.0
nM
|
|
Journal : J. Med. Chem.
Title : Tricyclic compounds as selective antimuscarinics. 1. Structural requirements for selectivity toward the muscarinic acetylcholine receptor in a series of pirenzepine and imipramine analogues.
Year : 1987
Volume : 30
Issue : 8
First Page : 1378
Last Page : 1382
Authors : Eberlein WG, Trummlitz G, Engel WW, Schmidt G, Pelzer H, Mayer N.
Abstract : The M1-selective antiulcer drug pirenzepine (1) is a tricyclic compound with close resemblance to tricyclic psychotropic agents such as imipramine (2). Despite this fact, pirenzepine is devoid of any psychotropic effects, exhibiting measurable antagonistic effects in biochemical assays and receptor binding studies only toward the muscarinic receptor system. To understand how different groups in these tricyclic molecules affect binding affinities, a set of nine compounds structurally related to pirenzepine (1) and imipramine (2) has been selected for analysis, comprising three different tricycles and three different side chains. The compounds were tested for their affinity to the imipramine and muscarinic receptors in homogenized rat cortex tissue. The result of these studies suggests that it is the nature and placement of accessory groups that determine the differences in receptor recognition and the binding process. In the case of pirenzepine (1), preferential binding toward the muscarinic receptor is brought about by the endocyclic amide group, by the positioning of the protonated N atom of the side chain, and to a minor extent by the exocyclic amide group. From these findings a putative model for the explanation of selective binding of pirenzepine (1) to the muscarinic receptor has been derived.
|
Binding affinity towards muscarinic acetylcholine receptor by inhibiting specific binding of [3H]quinuclidinyl benzilate (0.8 nM) in vitro to membranes of rat brain without cerebellum
|
None
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : cis-1,3,4,6,7,11b-Hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a] isoquinoline: a new atypical antidepressant.
Year : 1984
Volume : 27
Issue : 8
First Page : 995
Last Page : 1003
Authors : Griffith RC, Gentile RJ, Robichaud RC, Frankenheim J.
Abstract : Molecular modelling studies suggested the synthesis of cis-1,3,4,6,7, 11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline (7a) as a rigid analogue of the atypical antidepressant mianserin. Acylation of 2,2-diphenylethylamine with chloroacetyl chloride gives the chloroacetamide (2). Cyclization of 2 with P2O5 in xylene provides 1-(chloromethyl)-3,4-dihydro-4-phenylisoquinoline (3). Amination of 3, followed by reduction, gives the isomeric (aminomethyl)tetrahydroisoquinolines (4a and 5). Treatment of 4a with diethyl oxalate, followed by reduction of the diamide with borane, provides 7a. A variety of N-substituted, aromatic substituted, and optically resolved derivatives were prepared and evaluated for anticholinergic, antihistaminic, and antidepressant activity. In particular, the target cis isomer 7a as predicted from the modelling studies appears to possess excellent atypical antidepressant activity. This activity resides in the (+)-S,S optical isomer 10, which has the same absolute configuration as (+)-mianserin.
|
Binding affinity to Norepinephrine transporter using [3H]-nisoxatine as radioligand in stably transfected NIH3T3 cells
|
None
|
16.0
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.
|
Binding affinity towards Norepinephrine transporter using [3H]nisoxitine as radioligand
|
None
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural determinants for high 5-HT(2A) receptor affinity of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (SpAMDA).
Year : 2004
Volume : 14
Issue : 9
First Page : 2279
Last Page : 2283
Authors : Peddi S, Roth BL, Glennon RA, Westkaemper RB.
Abstract : The synthesis and 5-HT(2A) receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (4), a structurally unique tetracyclic 5-HT(2A) receptor antagonist, are described. The characteristics of the parent compound prove to be necessary for optimal 5-HT(2A) receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce compounds with reasonably high 5-HT(2A) receptor affinities. In addition, the parent compound is shown to have high 5-HT(2) receptor selectivity.
|
Compound was tested for its inhibitory activity against Noradrenaline receptor
|
Rattus norvegicus
|
46.0
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.
|
Concentration of compound to inhibit 50% of [3H]norepinephrine neurotransmitter uptake in rat brain
|
Rattus norvegicus
|
169.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogues.
Year : 1980
Volume : 23
Issue : 8
First Page : 865
Last Page : 873
Authors : Martin AR, Paradkar VM, Peng GW, Speth RC, Yamamura HI, Horn AS.
|
Concentration of compound to inhibit 50% of [3H]-5-HT neurotransmitter uptake in rat brain
|
Rattus norvegicus
|
384.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogues.
Year : 1980
Volume : 23
Issue : 8
First Page : 865
Last Page : 873
Authors : Martin AR, Paradkar VM, Peng GW, Speth RC, Yamamura HI, Horn AS.
|
Concentration required for its norepinephrine reuptake inhibitory activity in synaptosomal rat hyphalamic preparations
|
Rattus norvegicus
|
105.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological characterization of ABT-200: a putative novel antidepressant combining potent -2 antagonism with moderate NE uptake inhibition
Year : 1994
Volume : 4
Issue : 11
First Page : 1319
Last Page : 1322
Authors : Zelle RE, Hancock AA, Buckner SA, Basha FZ, Tietje K, DeBernardis JF, Meyer MD
|
In vitro inhibitory activity against [3H]5-HT uptake into crude synaptosomes from whole rat brain.
|
Rattus norvegicus
|
240.0
nM
|
|
Journal : J. Med. Chem.
Title : 3,4-Diphenyl-1H-pyrazole-1-propanamine antidepressants.
Year : 1985
Volume : 28
Issue : 2
First Page : 256
Last Page : 260
Authors : Bailey DM, Hansen PE, Hlavac AG, Baizman ER, Pearl J, DeFelice AF, Feigenson ME.
Abstract : A small series of compounds is described in which a narrow SAR has identified N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine, 3, as a potential antidepressant with reduced side effects. The isomeric N,N-dimethyl-4,5-diphenyl-1H-pyrazole-1-propanamine was completely inactive in the primary antidepressant screens. Compounds were synthesized by Michael addition of acrylonitrile to diphenylpyrazole followed by reductive alkylation of the resultant diphenylpyrazolepropionitriles. Compound 3 was equipotent with imipramine in standard antidepressant assays in animals but showed no significant anticholinergic action and did not antagonize the antihypertensive effects of clonidine and guanethidine.
|
Inhibition of 5-HT uptake in synaptosomal preparation from rat corpus striatum, using [3H]5-HT
|
Rattus norvegicus
|
810.0
nM
|
|
Journal : J. Med. Chem.
Title : Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins.
Year : 1984
Volume : 27
Issue : 11
First Page : 1508
Last Page : 1515
Authors : Welch WM, Kraska AR, Sarges R, Koe BK.
Abstract : The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants has prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy. The potential role of derangements of 5-HT pathways in the etiology of depression has long been suspected and has given impetus to the development of newer compounds that accentuate inhibition of serotonin reuptake. This paper presents structure-activity relationships for a series of cis-1-amino-4-(substituted-aryl)tetralins, which are surprisingly potent and selective inhibitors of serotonin uptake in in vitro models. These compounds are pharmacologically distinct from corresponding members of the trans series, which also potently block uptake of dopamine and norepinephrine. The activity in both cis and trans series is stereospecific, being restricted to the cis-(1S,4S) and the trans-(1R,4S) enantiomers.
|
Inhibition of Norepinephrine uptake from rat diencephalon-midbrain
|
Rattus norvegicus
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Orally active and potent inhibitors of gamma-aminobutyric acid uptake.
Year : 1985
Volume : 28
Issue : 5
First Page : 653
Last Page : 660
Authors : Ali FE, Bondinell WE, Dandridge PA, Frazee JS, Garvey E, Girard GR, Kaiser C, Ku TW, Lafferty JJ, Moonsammy GI.
Abstract : 3-Pyrrolidineacetic acid (1a), certain piperidinecarboxylic acids--i.e., 3-piperidinecarboxylic acid (2a), 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (3a), and cis-4-hydroxy-3-piperidinecarboxylic acid (4a)--cis-3-aminocyclohexanecarboxylic acid (5a, cis-3-ACHC), and gamma-aminobutyric acid (6a, GABA) itself are among the most potent inhibitors of [3H]GABA uptake by neurons and glia in vitro. These hydrophilic amino acids, however, do not readily enter the central nervous system in pharmacologically significant amounts following peripheral administration. We now report that N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (2b) is a specific GABA-uptake inhibitor that is more potent, more lipophilic and, in limited testing, as selective as 2a. Similar results were obtained with the N-(4,4-diphenyl-3-butenyl) derivatives of 1a, 3a, and 4a. By contrast, N-(4,4-diphenyl-3-butenyl) derivatives of 5a and 6a were not more potent than the parent amino acids and appear to inhibit GABA uptake, at least in part, by a nonselective mechanism of action. The N-(4,4-diphenyl-3-butenyl)amino acids 1b-4b exhibit anticonvulsant activity in rodents following oral or intraperitoneal administration [Yunger, L.M.; et al. J. Pharmacol. Exp. Ther. 1984, 228, 109].
|
Inhibition of norepinephrine uptake in synaptosomal preparation fro rat hypothalamus, using [3H]norepinephrine
|
None
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins.
Year : 1984
Volume : 27
Issue : 11
First Page : 1508
Last Page : 1515
Authors : Welch WM, Kraska AR, Sarges R, Koe BK.
Abstract : The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants has prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy. The potential role of derangements of 5-HT pathways in the etiology of depression has long been suspected and has given impetus to the development of newer compounds that accentuate inhibition of serotonin reuptake. This paper presents structure-activity relationships for a series of cis-1-amino-4-(substituted-aryl)tetralins, which are surprisingly potent and selective inhibitors of serotonin uptake in in vitro models. These compounds are pharmacologically distinct from corresponding members of the trans series, which also potently block uptake of dopamine and norepinephrine. The activity in both cis and trans series is stereospecific, being restricted to the cis-(1S,4S) and the trans-(1R,4S) enantiomers.
|
Inhibition of uptake of tritiated norepinephrine (NE) into rat brain synaptosomes
|
None
|
260.0
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.
|
Inhibition of uptake of tritiated serotonin (5-HT) into rat brain synaptosomes
|
None
|
120.0
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.
|
Inhibitory activity against uptake of [3H]norepinephrine into rat brain synaptosomes.
|
Rattus norvegicus
|
85.0
nM
|
|
Journal : J. Med. Chem.
Title : 1-Azacycloalkyl-1,4-benzodiazepin-2-ones with antianxiety-antidepressant actions.
Year : 1985
Volume : 28
Issue : 6
First Page : 699
Last Page : 707
Authors : Sugasawa T, Adachi M, Sasakura K, Matsushita A, Eigyo M, Shiomi T, Shintaku H, Takahara Y, Murata S.
Abstract : A series of 1-azacycloalkyl-1,4-benzodiazepin-2-ones were synthesized from 1-azacycloalkyl-2-benzoylanilines and corresponding imines and then evaluated for their central nervous system activities. Pharmacological data showed that some of these compounds have potent antidepressant properties, as assessed by their antagonism of tetrabenzine (TBZ) induced ptosis and their inhibition of [3H]norepinephrine uptake into rat brain synaptosomes, as well as their moderate antianxiety properties of preventing of pentylenetetrazol (PTZ) convulsion, suppressing conflict behavior, and displacing potential for [3H]diazepam binding. Introduction of a halogen substituent at position 7 of the 1,4-benzodiazepine ring lengthened the anti-PTZ effects, although the peak effect was slightly reduced and clearly enhanced the anti-PTZ and anticonflict properties. Introduction of Cl to the ortho position of the phenyl ring at position 5 greatly reduced the antidepressant properties. The secondary amine function of the azacyclic ring at position 1 was essential for the production of the antidepressant properties. Of these new series, 7-fluoro-5-(2-fluorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-1,4-benzodi azepin-2 -one has the potential to become a useful antidepressant drug with a moderate antianxiety property.
|
In vitro inhibition of 5-HT uptake in rat brain synaptosomes using [3H]- 5-hydroxytryptamine
|
Rattus norvegicus
|
230.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antidepressant activity of 4-aryltetrahydrothieno[2,3-c]pyridine derivatives.
Year : 1984
Volume : 27
Issue : 9
First Page : 1150
Last Page : 1155
Authors : Schneider CS, Weber KH, Daniel H, Bechtel WD, Boeke-Kuhn K.
Abstract : A series of substituted 4-aryltetrahydrothieno[2,3-c]pyridines was prepared by acid-catalyzed cyclization of 1-aryl-2-[(2-thienylmethyl)amino]ethanol derivatives. The compounds were examined for their antidepressant activity, as demonstrated by their ability to inhibit the uptake of norepinephrine (NE) and serotonin (5-HT) and to prevent tetrabenazine-induced ptosis (TBZ) in mice. Significant inhibition of both neurotransmitters is observed for several of the tested compounds, while some of them are selective inhibitors of either NE or 5-HT uptake. Optimal activity is associated with the introduction of lipophilic substituents into the 4-position of the phenyl ring and less lipophilic substituents into the 2-position of the thiophene ring (11, 23). Compound 33 bearing substituents in positions 2 and 6 of the phenyl ring is inactive. This might be a consequence of an out of plane conformation of this compound.
|
Inhibition of GABA uptake from rat diencephalon-midbrain at 100 uM concentration
|
Rattus norvegicus
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : Orally active and potent inhibitors of gamma-aminobutyric acid uptake.
Year : 1985
Volume : 28
Issue : 5
First Page : 653
Last Page : 660
Authors : Ali FE, Bondinell WE, Dandridge PA, Frazee JS, Garvey E, Girard GR, Kaiser C, Ku TW, Lafferty JJ, Moonsammy GI.
Abstract : 3-Pyrrolidineacetic acid (1a), certain piperidinecarboxylic acids--i.e., 3-piperidinecarboxylic acid (2a), 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (3a), and cis-4-hydroxy-3-piperidinecarboxylic acid (4a)--cis-3-aminocyclohexanecarboxylic acid (5a, cis-3-ACHC), and gamma-aminobutyric acid (6a, GABA) itself are among the most potent inhibitors of [3H]GABA uptake by neurons and glia in vitro. These hydrophilic amino acids, however, do not readily enter the central nervous system in pharmacologically significant amounts following peripheral administration. We now report that N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (2b) is a specific GABA-uptake inhibitor that is more potent, more lipophilic and, in limited testing, as selective as 2a. Similar results were obtained with the N-(4,4-diphenyl-3-butenyl) derivatives of 1a, 3a, and 4a. By contrast, N-(4,4-diphenyl-3-butenyl) derivatives of 5a and 6a were not more potent than the parent amino acids and appear to inhibit GABA uptake, at least in part, by a nonselective mechanism of action. The N-(4,4-diphenyl-3-butenyl)amino acids 1b-4b exhibit anticonvulsant activity in rodents following oral or intraperitoneal administration [Yunger, L.M.; et al. J. Pharmacol. Exp. Ther. 1984, 228, 109].
|
Maximum inhibition of immobility in the rat (Expressed as percentage of immobility observed in vehicle controls)
|
Rattus norvegicus
|
31.0
%
|
|
Journal : J. Med. Chem.
Title : Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors.
Year : 1999
Volume : 42
Issue : 9
First Page : 1648
Last Page : 1660
Authors : Vacher B, Bonnaud B, Funes P, Jubault N, Koek W, Assié MB, Cosi C, Kleven M.
Abstract : The aim of this work was to improve the oral bioavailability of a recently discovered, novel structural class of 5-HT1A receptor agonists: aryl-{[4-(6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1 -yl-metha none. Incorporation of a fluorine atom in the beta-position to the amino function in the side chain led to analogues that exhibited, in general, enhanced and long-lasting 5-HT1A agonist activity in rats after oral administration. Location of the fluorine atom at the C-4 position of the piperidine ring was the most favorable, and among the various substituents tested, the ability of the fluorine was unique in improving the oral activity of this family of ligands. Thus, the derivatives 39, 46, and 61 bound with higher affinity and selectivity to 5-HT1A receptors (versus dopaminergic D2 and adrenergic alpha1 receptors) and displayed more potent 5-HT1A agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To examine the relationship between the conformation of the pharmacophore and the level of agonistic activity of this type of ligand, we synthesized a series of 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-(H or CH3)-6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-+ ++methanone derivatives and found that the combination of a 5-methyl and a 6-methylamino substituent on the pyridine ring synergistically affected their 5-HT1A agonist properties. Thus, the 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-6-methylamino-pyridin- 2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone 40 behaved as a more potent 5-HT1A receptor agonist in vitro and in vivo than its 5-unsubstituted analogue 38. The antidepressant potential of the lead compounds 40, 45, and 54 was examined by means of the forced swimming test (FST) in rats. The results indicated that, after a single oral administration, these compounds inhibited immobility in the FST more potently and more extensively than the clinically used antidepressant imipramine. Thus, 40, 45, and 54 are potent, orally active 5-HT1A receptor agonists with marked antidepressant potential.
|
In vitro inhibition of norepinephrine (NE) uptake in synaptosomal preparation of rat brain
|
Rattus norvegicus
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol: a novel antidepressant agent and selective inhibitor of norepinephrine uptake.
Year : 1996
Volume : 39
Issue : 2
First Page : 347
Last Page : 349
Authors : Kelley JL, Musso DL, Boswell GE, Soroko FE, Cooper BR.
|
In vitro inhibition of serotonin uptake in synaptosomal preparation of rat brain
|
Rattus norvegicus
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol: a novel antidepressant agent and selective inhibitor of norepinephrine uptake.
Year : 1996
Volume : 39
Issue : 2
First Page : 347
Last Page : 349
Authors : Kelley JL, Musso DL, Boswell GE, Soroko FE, Cooper BR.
|
Inhibition of [3H]dopamine uptake into rat brain synaptosomes in vitro;Values ranges from: 0.09-0.18
|
Rattus norvegicus
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antidepressant properties of novel 2-substituted 4,5-dihydro-1H-imidazole derivatives.
Year : 1987
Volume : 30
Issue : 8
First Page : 1482
Last Page : 1489
Authors : Wentland MP, Bailey DM, Alexander EJ, Castaldi MJ, Ferrari RA, Haubrich DR, Luttinger DA, Perrone MH.
Abstract : A unique combination of alpha 2-adrenoreceptor antagonist and serotonin-selective reuptake inhibitory activities has been identified in a series of 2-substituted 4,5-dihydro-1H-imidazole derivatives. This combination of blocking activities has provided one of these derivatives, napamezole hydrochloride (2), with potential as an antidepressant. A discussion of the syntheses of these compounds includes a convenient method for the conversion of nitriles to imidazolines with ethylenediamine and trimethylaluminum.
|
Inhibition of [3H]norepinephrine uptake into rat brain synaptosomes in vitro;Values ranges from: 0.01-0.07
|
Rattus norvegicus
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antidepressant properties of novel 2-substituted 4,5-dihydro-1H-imidazole derivatives.
Year : 1987
Volume : 30
Issue : 8
First Page : 1482
Last Page : 1489
Authors : Wentland MP, Bailey DM, Alexander EJ, Castaldi MJ, Ferrari RA, Haubrich DR, Luttinger DA, Perrone MH.
Abstract : A unique combination of alpha 2-adrenoreceptor antagonist and serotonin-selective reuptake inhibitory activities has been identified in a series of 2-substituted 4,5-dihydro-1H-imidazole derivatives. This combination of blocking activities has provided one of these derivatives, napamezole hydrochloride (2), with potential as an antidepressant. A discussion of the syntheses of these compounds includes a convenient method for the conversion of nitriles to imidazolines with ethylenediamine and trimethylaluminum.
|
Inhibition of [3H]5-HT uptake into rat brain synaptosomes in vitro;Values ranges from: 0.14-0.22
|
Rattus norvegicus
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antidepressant properties of novel 2-substituted 4,5-dihydro-1H-imidazole derivatives.
Year : 1987
Volume : 30
Issue : 8
First Page : 1482
Last Page : 1489
Authors : Wentland MP, Bailey DM, Alexander EJ, Castaldi MJ, Ferrari RA, Haubrich DR, Luttinger DA, Perrone MH.
Abstract : A unique combination of alpha 2-adrenoreceptor antagonist and serotonin-selective reuptake inhibitory activities has been identified in a series of 2-substituted 4,5-dihydro-1H-imidazole derivatives. This combination of blocking activities has provided one of these derivatives, napamezole hydrochloride (2), with potential as an antidepressant. A discussion of the syntheses of these compounds includes a convenient method for the conversion of nitriles to imidazolines with ethylenediamine and trimethylaluminum.
|
Inhibition of uptake of tritiated norepinephrine (NE) in rat synaptosomes
|
None
|
12.0
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.
|
Inhibition the uptake of tritiated serotonin (5-HT) by the serotonin transporter SERT in rat synaptosomes
|
None
|
41.8
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.
|
Binding affinity towards serotonin S1 receptor at 1.0 uM
|
Rattus norvegicus
|
15.0
%
|
|
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.
|
Binding affinity to Serotonin transporter using [3H]-paroxetine as radioligand in stably transfected NIH3T3 cells
|
None
|
5.0
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.
|
Binding affinity towards Serotonin transporter using [3H]paroxetine as radioligand
|
None
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structural determinants for high 5-HT(2A) receptor affinity of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (SpAMDA).
Year : 2004
Volume : 14
Issue : 9
First Page : 2279
Last Page : 2283
Authors : Peddi S, Roth BL, Glennon RA, Westkaemper RB.
Abstract : The synthesis and 5-HT(2A) receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (4), a structurally unique tetracyclic 5-HT(2A) receptor antagonist, are described. The characteristics of the parent compound prove to be necessary for optimal 5-HT(2A) receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce compounds with reasonably high 5-HT(2A) receptor affinities. In addition, the parent compound is shown to have high 5-HT(2) receptor selectivity.
|
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
|
72.7
%
|
|
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.
|
Binding affinity towards alpha-1 adrenergic receptor
|
None
|
220.0
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.
|
Percent inhibition against 5-hydroxytryptamine transporter at 1 uM nonselective
|
Homo sapiens
|
4.4
nM
|
|
Journal : J. Med. Chem.
Title : 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization.
Year : 2005
Volume : 48
Issue : 22
First Page : 6887
Last Page : 6896
Authors : Minetti P, Tinti MO, Carminati P, Castorina M, Di Cesare MA, Di Serio S, Gallo G, Ghirardi O, Giorgi F, Giorgi L, Piersanti G, Bartoccini F, Tarzia G.
Abstract : Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, to obtain selective A(2A) antagonists, and we report here their synthesis and binding affinities for the four adenosine receptor subtypes A(1), A(2A), A(2B) and A(3). The design was carried out on the basis of the molecular modeling of a number of potent adenosine receptor antagonists described in the literature. Three compounds (25b-d) showed an interesting affinity and selectivity for the A(2A) subtype. One of them, i.e., ST1535 (2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine, 25b) (K(i) A(2A) = 6.6 nM, K(i) A(1)/A(2A) = 12; K(i) A(2B)/A(2A) = 58; K(i) A(3)/A(2A) > 160), was selected for in vivo study and shown to induce a dose-related increase in locomotor activity, suggestive of an A(2A) antagonist type of activity.
|
Displacement of [3H]citalopram from serotonin transporter
|
None
|
20.3
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 radiolabeled imipramine from human SERT
|
Homo sapiens
|
6.9
nM
|
|
Displacement of radiolabeled imipramine from human SERT
|
Homo sapiens
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia.
Year : 2008
Volume : 51
Issue : 22
First Page : 7094
Last Page : 7098
Authors : Liu H, Altenbach RJ, Carr TL, Chandran P, Hsieh GC, Lewis LG, Manelli AM, Milicic I, Marsh KC, Miller TR, Strakhova MI, Vortherms TA, Wakefield BD, Wetter JM, Witte DG, Honore P, Esbenshade TA, Brioni JD, Cowart MD.
Abstract : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.
|
Inhibition of [3H]5HT uptake at human SERT expressed in HEK293 cells
|
Homo sapiens
|
8.0
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
|
74.0
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 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
82.8
%
|
|
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.
|
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]serotonin reuptake at serotonin transporter
|
None
|
7.57
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 human 5-HT transporter
|
Homo sapiens
|
7.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.
Year : 2010
Volume : 18
Issue : 21
First Page : 7675
Last Page : 7699
Authors : Hayashi S, Nakata E, Morita A, Mizuno K, Yamamura K, Kato A, Ohashi K.
Abstract : Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.
|
Displacement of [3H]imipramine from human 5HT transporter
|
Homo sapiens
|
0.77
nM
|
|
Journal : J. Med. Chem.
Title : Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators.
Year : 2011
Volume : 54
Issue : 15
First Page : 5320
Last Page : 5334
Authors : Dolusić E, Larrieu P, Moineaux L, Stroobant V, Pilotte L, Colau D, Pochet L, Van den Eynde B, Masereel B, Wouters J, Frédérick R.
Abstract : Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.
|
Inhibition of human OCT2 expressed in HEK-293-Flp-In cells incubated for 3 mins by ASP+ substrate uptake assay
|
Homo sapiens
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.
Year : 2011
Volume : 54
Issue : 13
First Page : 4548
Last Page : 4558
Authors : Kido Y, Matsson P, Giacomini KM.
Abstract : Drug-drug interactions (DDIs) are major causes of serious adverse drug reactions. Most DDIs have a pharmacokinetic basis in which one drug reduces the elimination of a second drug, leading to potentially toxic drug levels. As a major organ of drug elimination, the kidney represents an important site for DDIs. Here, we screened a prescription drug library against the renal organic cation transporter OCT2/SLC22A2, which mediates the first step in the renal secretion of many cationic drugs. Of the 910 compounds screened, 244 inhibited OCT2. Computational analyses revealed key properties of inhibitors versus noninhibitors, which included overall molecular charge. Four of six potential clinical inhibitors were transporter-selective in follow-up screens against additional transporters: OCT1/SLC22A1, MATE1/SLC47A1, and MATE2-K/SLC47A2. Two compounds showed different kinetics of interaction with the common polymorphism OCT2-A270S, suggesting a role of genetics in modulating renal DDIs.
|
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
|
26.9
%
|
|
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
|
-2.4
%
|
|
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 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
|
16.9
%
|
|
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 SERT expressed in HEK293-MSR cells by 5-HT uptake assay
|
Homo sapiens
|
29.0
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.
|
Binding affinity to human serotonin 5-HT transporter by radioligand displacement assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide stereoisomers as novel positive allosteric modulators of sigma-1 receptor.
Year : 2013
Volume : 21
Issue : 10
First Page : 2764
Last Page : 2771
Authors : Veinberg G, Vorona M, Zvejniece L, Vilskersts R, Vavers E, Liepinsh E, Kazoka H, Belyakov S, Mishnev A, Kuznecovs J, Vikainis S, Orlova N, Lebedev A, Ponomaryov Y, Dambrova M.
Abstract : Novel positive allosteric modulators of sigma-1 receptor represented by 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide enantiomers were synthesised using an asymmetric Michael addition of 2-nitroprop-1-enylbenzene to diethyl malonate. Following the chromatographic separation of the methyl erythro- and threo-4-nitro-3R- and 3S-phenylpentanoate diastereoisomers, target compounds were obtained by their reductive cyclisation into 5-methyl-4-phenylpyrrolidin-2-one enantiomers and the attachment of the acetamide group to the heterocyclic nitrogen. Experiments with electrically stimulated rat vas deference contractions induced by the PRE-084, an agonist of sigma-1 receptor, showed that (4R,5S)- and (4R,5R)-2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamides with an R-configuration at the C-4 chiral centre in the 2-pyrrolidone ring were more effective positive allosteric modulators of sigma-1 receptor than were their optical antipodes.
|
Binding affinity to human 5-HT transporter by radioligand displacement assay
|
Homo sapiens
|
0.52
nM
|
|
Binding affinity to human 5-HT transporter by radioligand displacement assay
|
Homo sapiens
|
1.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship studies in serotonin 5-HT(1A) receptor agonists based on fused pyrrolidone scaffolds.
Year : 2013
Volume : 63
First Page : 85
Last Page : 94
Authors : Cappelli A, Manini M, Valenti S, Castriconi F, Giuliani G, Anzini M, Brogi S, Butini S, Gemma S, Campiani G, Giorgi G, Mennuni L, Lanza M, Giordani A, Caselli G, Letari O, Makovec F.
Abstract : A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate γ-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT1AR.
|
Displacement of [3H]imipramin from human recombinant SERT over-expressed in HEK293 cells
|
Homo sapiens
|
6.8
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.
|
Binding affinity to SERT (unknown origin) by radioligand binding assay
|
Homo sapiens
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
|
Binding affinity to 5HT2A receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
|
Binding affinity to dopamine D2 receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
410.0
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
|
Binding affinity to histamine H1 receptor (unknown origin) by radioligand binding assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Polypharmacology - foe or friend?
Year : 2013
Volume : 56
Issue : 22
First Page : 8955
Last Page : 8971
Authors : Peters JU.
Abstract : Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
|
Analgesic activity in mouse assessed as inhibition of acetic acid-induced writhing response at 30 mg/kg, po administered 30 mins prior to acetic acid-challenge relative to control
|
Mus musculus
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis of spiro[tetralin-2,2'-pyrrolidine] and spiro[indan-2,2'-pyrrolidine] derivatives as potential analgesics.
Year : 1978
Volume : 21
Issue : 6
First Page : 585
Last Page : 587
Authors : Crooks PA, Rosenberg HE.
Abstract : Spiro[tetralin-2,2'-pyrrolidine] (13) and spiro[6-methoxytetralin-2,2'-pyrrolidine] (17) were prepared by initial Michael condensation of 2-nitrotetralin and 6-methoxy-2-nitrotetralin, respectively, with methyl acrylate to give 7 and 8, both of which could be reductively cyclized to 10 and 11, followed by LiAlH4 reduction. Spiro[indan-2,2'-pyrrolidine] (15) was prepared in an analogous manner form 2-nitroindan, and spiro[6-hydroxytetralin-2,2'-pyrrolidine] (19) was prepared by O-demethylation of 17. Compound 13 and its N-methyl derivative, 14, both showed good analgesic activity. Compounds 13-16 all possessed weak antidepressant properties, but neither 19 nor its N-methyl derivative 20 had any significant CNS activity.
|
Anticholinergic effect in guinea pig ileum assessed as inhibition of acetylcholine-induced contraction
|
Cavia porcellus
|
1.259
nM
|
|
Journal : J. Med. Chem.
Title : Substituted 3-amino-1,1-diaryl-2-propanols as potential antidepressant agents.
Year : 1979
Volume : 22
Issue : 11
First Page : 1373
Last Page : 1379
Authors : Clark JA, Clark MS, Gardner DV, Gaster LM, Hadley MS, Miller D, Shah A.
Abstract : Following the discovery that 3-(dimethylamino)-1,1-diphenyl-2-propanol hydrobromide (1) possesses potent reserpine-prevention activity in mice, a series of analogues of 1 was synthesized and evaluated as potential antidepressant agents. Several routes to analogues of 1 were evaluated, the most generally applicable of which was the regiospecific ring opening of a suitably functionalized 1,1-diaryl-2,3-epoxypropane (obtained in three stages from the corresponding benzophenone) with the appropriate amine. The more interesting compounds of the series were evaluated for their propensity to cause undesirable peripheral anticholinergic effects, all compounds tested being markedly less active than imipramine on this parameter. On the basis of its good activity in biochemical and pharmacological animal models of depression, together with its relative lack of anticholinergic side effects, 1-(3-chlorophenyl)-3-(dimethylamino)-1-phenyl-2-propanol hydrochloride (20, BRL 14342) was chosen for further evaluation.
|
Displacement of [3H]imipramine from human recombinant SERT expressed in CHO cells
|
Homo sapiens
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Novel arylsulfonamide derivatives with 5-HT₆/5-HT₇ receptor antagonism targeting behavioral and psychological symptoms of dementia.
Year : 2014
Volume : 57
Issue : 11
First Page : 4543
Last Page : 4557
Authors : Kołaczkowski M, Marcinkowska M, Bucki A, Pawłowski M, Mitka K, Jaśkowska J, Kowalski P, Kazek G, Siwek A, Wasik A, Wesołowska A, Mierzejewski P, Bienkowski P.
Abstract : In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population.
|
Displacement of [3H]imipramine from human SERT expressed in CHO cells
|
Homo sapiens
|
2.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia.
Year : 2015
Volume : 92
First Page : 221
Last Page : 235
Authors : Kołaczkowski M, Marcinkowska M, Bucki A, Śniecikowska J, Pawłowski M, Kazek G, Siwek A, Jastrzębska-Więsek M, Partyka A, Wasik A, Wesołowska A, Mierzejewski P, Bienkowski P.
Abstract : We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits.
|
Time dependent inhibition of CYP1A2 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2B6 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C9 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C19 in human liver microsomes at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2D6 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP3A4 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C8 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Displacement of [3H]imipramine from human recombinant 5-HT transporter expressed in CHO cells
|
Homo sapiens
|
0.88
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents.
Year : 2016
Volume : 24
Issue : 8
First Page : 1793
Last Page : 1810
Authors : Waszkielewicz AM, Gunia-Krzyżak A, Powroźnik B, Słoczyńska K, Pękala E, Walczak M, Bednarski M, Żesławska E, Nitek W, Marona H.
Abstract : A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.
|
Inhibition of wild-type human SERT expressed in HEK293 MSR cells assessed as [3H]-5-HT uptake preincubated for 30 mins followed addition of [3H]-5HT and compound for 10 mins by micro-scintillation counter
|
Homo sapiens
|
31.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter.
Year : 2016
Volume : 24
Issue : 12
First Page : 2725
Last Page : 2738
Authors : Brinkø A, Larsen MT, Koldsø H, Besenbacher L, Kolind A, Schiøtt B, Sinning S, Jensen HH.
Abstract : The human serotonin transporter is the primary target of several antidepressant drugs, and the importance of a primary, high affinity binding site (S1) for antidepressant binding is well documented. The existence of a lower affinity, secondary binding site (S2) has, however, been debated. Herein we report the synthesis of 3-position coupled imipramine ligands from clomipramine using a copper free Sonogashira reaction. Ligand design was inspired by results from docking and steered molecular dynamics simulations, and the ligands were utilized in a structure-activity relationship study of the positional relationship between the S1 and S2 sites. The computer simulations suggested that the S2 site does indeed exist although with lower affinity for imipramine than observed within the S1 site. Additionally, it was possible to dock the 3-linked imipramine analogs into positions which occupy the S1 and the S2 site simultaneously. The structure activity relationship study showed that the shortest ligands were the most potent, and mutations enlarging the proposed S2 site were found to affect the larger ligands positively, while the smaller ligands were mostly unaffected.
|
Inhibition of human SERT W103A mutant expressed in HEK293 MSR cells assessed as [3H]-5-HT uptake preincubated for 30 mins followed addition of [3H]-5HT and compound for 10 mins by micro-scintillation counter
|
Homo sapiens
|
2.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter.
Year : 2016
Volume : 24
Issue : 12
First Page : 2725
Last Page : 2738
Authors : Brinkø A, Larsen MT, Koldsø H, Besenbacher L, Kolind A, Schiøtt B, Sinning S, Jensen HH.
Abstract : The human serotonin transporter is the primary target of several antidepressant drugs, and the importance of a primary, high affinity binding site (S1) for antidepressant binding is well documented. The existence of a lower affinity, secondary binding site (S2) has, however, been debated. Herein we report the synthesis of 3-position coupled imipramine ligands from clomipramine using a copper free Sonogashira reaction. Ligand design was inspired by results from docking and steered molecular dynamics simulations, and the ligands were utilized in a structure-activity relationship study of the positional relationship between the S1 and S2 sites. The computer simulations suggested that the S2 site does indeed exist although with lower affinity for imipramine than observed within the S1 site. Additionally, it was possible to dock the 3-linked imipramine analogs into positions which occupy the S1 and the S2 site simultaneously. The structure activity relationship study showed that the shortest ligands were the most potent, and mutations enlarging the proposed S2 site were found to affect the larger ligands positively, while the smaller ligands were mostly unaffected.
|
Inhibition of human SERT I179C mutant expressed in HEK293 MSR cells assessed as [3H]-5-HT uptake preincubated for 30 mins followed addition of [3H]-5HT and compound for 10 mins by micro-scintillation counter
|
Homo sapiens
|
5.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and inhibitory evaluation of 3-linked imipramines for the exploration of the S2 site of the human serotonin transporter.
Year : 2016
Volume : 24
Issue : 12
First Page : 2725
Last Page : 2738
Authors : Brinkø A, Larsen MT, Koldsø H, Besenbacher L, Kolind A, Schiøtt B, Sinning S, Jensen HH.
Abstract : The human serotonin transporter is the primary target of several antidepressant drugs, and the importance of a primary, high affinity binding site (S1) for antidepressant binding is well documented. The existence of a lower affinity, secondary binding site (S2) has, however, been debated. Herein we report the synthesis of 3-position coupled imipramine ligands from clomipramine using a copper free Sonogashira reaction. Ligand design was inspired by results from docking and steered molecular dynamics simulations, and the ligands were utilized in a structure-activity relationship study of the positional relationship between the S1 and S2 sites. The computer simulations suggested that the S2 site does indeed exist although with lower affinity for imipramine than observed within the S1 site. Additionally, it was possible to dock the 3-linked imipramine analogs into positions which occupy the S1 and the S2 site simultaneously. The structure activity relationship study showed that the shortest ligands were the most potent, and mutations enlarging the proposed S2 site were found to affect the larger ligands positively, while the smaller ligands were mostly unaffected.
|
Inhibition of human SERT expressed in CHO cell membranes assessed as reduction in [3H]serotonin uptake preincubated for 10 mins followed by [3H]serotonin addition measured after 20 mins by liquid scintillation counting method
|
Homo sapiens
|
5.1
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect.
Year : 2017
Volume : 25
Issue : 1
First Page : 293
Last Page : 304
Authors : Yoshinaga H, Masumoto S, Koyama K, Kinomura N, Matsumoto Y, Kato T, Baba S, Matsumoto K, Horisawa T, Oki H, Yabuuchi K, Kodo T.
Abstract : We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.
|
Displacement of [3H]citalopram from human SERT expressed in HEK293 cell membranes after 1 hr by liquid scintillation counting method
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect.
Year : 2017
Volume : 25
Issue : 1
First Page : 293
Last Page : 304
Authors : Yoshinaga H, Masumoto S, Koyama K, Kinomura N, Matsumoto Y, Kato T, Baba S, Matsumoto K, Horisawa T, Oki H, Yabuuchi K, Kodo T.
Abstract : We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.
|
Displacement of [3H]imipramine from human recombinant 5HT transporter expressed in CHO cells measured after 60 mins by scintillation counting method
|
Homo sapiens
|
0.88
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3.
Year : 2017
Volume : 25
Issue : 2
First Page : 471
Last Page : 482
Authors : Gunia-Krzyżak A, Żelaszczyk D, Rapacz A, Żesławska E, Waszkielewicz AM, Pańczyk K, Słoczyńska K, Pękala E, Nitek W, Filipek B, Marona H.
Abstract : A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50 MES=53.76, ED50 scPTZ=90.31, ED50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50 MES=55.58, ED50 scPTZ=102.15, ED50 6-Hz 44mA=51.27mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives.
|
Displacement of [3H]-imipramine from human serotonin transporter expressed in HEK-293 cell membranes after 30 mins by scintillation counting
|
Homo sapiens
|
1.0
nM
|
|
Journal : J Med Chem
Title : Novel 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole-Based Multifunctional Ligands with Antipsychotic-Like, Mood-Modulating, and Procognitive Activity.
Year : 2017
Volume : 60
Issue : 17
First Page : 7483
Last Page : 7501
Authors : Bucki A, Marcinkowska M, Śniecikowska J, Więckowski K, Pawłowski M, Głuch-Lutwin M, Gryboś A, Siwek A, Pytka K, Jastrzębska-Więsek M, Partyka A, Wesołowska A, Mierzejewski P, Kołaczkowski M.
Abstract : The most troublesome aspects of behavioral and psychological symptoms of dementia (BPSD) are nowadays addressed by antidepressant, anxiolytic, and antipsychotic drugs, often administered off-label. Considering their modest effectiveness in dementia patients, the increased risk of adverse events and cognitive decline, there is an unmet need for well-tolerated and effective therapy of BPSD. We designed and synthesized multifunctional ligands characterized in vitro as high-affinity partial agonists of D2R, antagonists of 5-HT6R, and blockers of SERT. Moreover, the molecules activated 5-HT1AR and blocked 5-HT7R while having no relevant affinity for off-target M1R and hERG channel. Compound 16 (N-{2-[4-(5-chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl}-3-methylbenzene-1-sulfonamide) exhibited a broad antipsychotic-, antidepressant-, and anxiolytic-like activity, not eliciting motor impairments in mice. Most importantly, 16 showed memory-enhancing properties and it ameliorated memory deficits induced by scopolamine. The molecule outperformed most important comparators in selected tests, indicating its potential in the treatment of both cognitive and noncognitive (behavioral and psychological) symptoms of dementia.
|
Inhibition of SERT expressed in rat brain synaptosomes assessed as decrease in incorporation of [3H]serotonin measured after 15 mins by scintillation counting method
|
Rattus norvegicus
|
61.0
nM
|
|
Journal : J Med Chem
Title : Novel 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole-Based Multifunctional Ligands with Antipsychotic-Like, Mood-Modulating, and Procognitive Activity.
Year : 2017
Volume : 60
Issue : 17
First Page : 7483
Last Page : 7501
Authors : Bucki A, Marcinkowska M, Śniecikowska J, Więckowski K, Pawłowski M, Głuch-Lutwin M, Gryboś A, Siwek A, Pytka K, Jastrzębska-Więsek M, Partyka A, Wesołowska A, Mierzejewski P, Kołaczkowski M.
Abstract : The most troublesome aspects of behavioral and psychological symptoms of dementia (BPSD) are nowadays addressed by antidepressant, anxiolytic, and antipsychotic drugs, often administered off-label. Considering their modest effectiveness in dementia patients, the increased risk of adverse events and cognitive decline, there is an unmet need for well-tolerated and effective therapy of BPSD. We designed and synthesized multifunctional ligands characterized in vitro as high-affinity partial agonists of D2R, antagonists of 5-HT6R, and blockers of SERT. Moreover, the molecules activated 5-HT1AR and blocked 5-HT7R while having no relevant affinity for off-target M1R and hERG channel. Compound 16 (N-{2-[4-(5-chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl}-3-methylbenzene-1-sulfonamide) exhibited a broad antipsychotic-, antidepressant-, and anxiolytic-like activity, not eliciting motor impairments in mice. Most importantly, 16 showed memory-enhancing properties and it ameliorated memory deficits induced by scopolamine. The molecule outperformed most important comparators in selected tests, indicating its potential in the treatment of both cognitive and noncognitive (behavioral and psychological) symptoms of dementia.
|
Displacement of [3H]-imipramine from human serotonin transporter expressed in HEK293 cells membranes incubated for 30 mins by microbeta scintillation counting analysis
|
Homo sapiens
|
2.5
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect.
Year : 2019
Volume : 183
First Page : 111736
Last Page : 111736
Authors : Wróbel MZ, Chodkowski A, Herold F, Marciniak M, Dawidowski M, Siwek A, Starowicz G, Stachowicz K, Szewczyk B, Nowak G, Belka M, Bączek T, Satała G, Bojarski AJ, Turło J.
Abstract : A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT<sub>1A</sub>/D<sub>2</sub>/5-HT<sub>2A</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT<sub>1A</sub> receptors (e.g., 4cK<sub>i</sub> = 2.3 nM, 4lK<sub>i</sub> = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT<sub>1A</sub> receptor) exhibited promising affinities for the 5-HT<sub>1A</sub>/SERT/D<sub>2</sub>/5-HT<sub>6</sub>/5-HT<sub>7</sub> receptors and showed an antidepressant-like activity in the FST model.
|
Displacement of [3H]-citalopram from SERT in rat cortex tissue incubated for 60 mins by microbeta scintillation counting method
|
Rattus norvegicus
|
29.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of new 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT<sub>1A</sub> receptor ligands.
Year : 2019
Volume : 180
First Page : 383
Last Page : 397
Authors : Ślifirski G, Król M, Kleps J, Podsadni P, Belka M, Bączek T, Siwek A, Stachowicz K, Szewczyk B, Nowak G, Bojarski A, Kozioł AE, Turło J, Herold F.
Abstract : Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives. In vitro tests (RBA) were carried out for 10.1-10.27 compounds in order to determine their affinity to 5-HT<sub>1A</sub> receptor and SERT protein. 10.1-10.3, 10.6, 10.7, 10.16 and 10.27 compounds had high binding ability to both molecular targets (5-HT<sub>1A</sub> K<sub>i</sub> = 8-87 nM; SERT K<sub>i</sub> = 8-52 nM). For these compounds (10.1-10.3, 10.6, 10.7, 10.16, 10.27) further in vitro, in vivo and metabolic stability tests were performed. In vitro studies in the extended receptor profile (D<sub>2</sub>, 5-HT<sub>2A</sub>, 5-HT<sub>6</sub> and 5-HT<sub>7</sub>) showed their selectivity towards 5-HT<sub>1A</sub> receptor and SERT protein. In vivo tests revealed that compounds 10.7 and 10.16 had the properties of presynaptic antagonists of the 5-HT<sub>1A</sub> receptor. The redesign of the 2H-pyrido[1,2-c]pyrimidine residue present in the terminal part towards 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine resulted in the improved metabolic stability and enhanced affinity to both molecular targets (5-HT<sub>1A</sub>-R and SERT) compared to the precursors.
|
Displacement of [3H] imipramine from human recombinant 5-HT transporter measured after 60 mins by scintillation counter method
|
Homo sapiens
|
1.9
nM
|
|
Displacement of [3H] imipramine from human recombinant 5-HT transporter measured after 60 mins by scintillation counter method
|
Homo sapiens
|
4.1
nM
|
|
Journal : Eur J Med Chem
Title : Multi-targeting protein-protein interaction inhibitors: Evolution of macrocyclic ligands with embedded carbohydrates (MECs) to improve selectivity.
Year : 2019
Volume : 176
First Page : 292
Last Page : 309
Authors : Negi A, Reilly CO, Jarikote DV, Zhou J, Murphy PV.
Abstract : Compounds targeting multiple proteins can have synergistic effects and are therefore of interest in medicinal chemistry. At the same time, inhibiting protein-protein interactions (PPI) is increasingly desired in the treatment of disorders or diseases. The development of non-peptidomimetic inhibitors is still a challenge. Herein we investigate macrocyclic scaffolds with one or two embedded carbohydrates (MECs) that present amino acid side chains, or related isosteres, as pharmacophoric groups. Firstly, retroscreening of the previously reported eannaphane-40 (E40, 40), a MEC presenting two pharmacophoric groups, against a set of 55 receptor-subtypes led to a finding of sub-micromolar inhibitory activity for E40 against three serotonergic isoforms (5HT1A/2A/2B) as well as the Na+ channel and the NK-2 receptor. We synthesised MECs with an additional pharmacophoric group compared to E40, with a view to identifying compounds where the selectivity profile was altered among the protein hits from the retroscreening. MECs were produced based on scaffolds with two monosaccharide residues, leading to the incorporation of a third pharmacophoric group. Later, homology models were prepared for four proteins (5HT1A, 5HT2A, NK2 and site-2 of the sodium channel) whose 3D structure is unknown. Inverse docking of the synthesised compounds led to the selection of a new MEC (MEC-B) for protein binding assays. MEC-B was found to have its selectivity profile modulated, in line with docking prediction, compared to E40. MEC-B is dual inhibitor of both 5-HT1A and the sodium channel with improved selectivity for these proteins compared to 5-HT2A/2B/2C, 5-HT transporter and NK2 receptor. Thus, a new multitargeting compound, with an improved selectivity profile was identified, based on a MEC peptidomimetic scaffold.
|
Displacement of [3H]-citalopram from SERT in rat cortex tissue measured after 60 mins by microbeta scintillation counting analysis
|
Rattus norvegicus
|
29.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of novel pyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands.
Year : 2019
Volume : 166
First Page : 144
Last Page : 158
Authors : Ślifirski G, Król M, Kleps J, Ulenberg S, Belka M, Bączek T, Siwek A, Stachowicz K, Szewczyk B, Nowak G, Bojarski A, Kozioł AE, Turło J, Herold F.
Abstract : The study enabled obtaining a number of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine 9.1-9.27 having conformationally restricted tryptamine moiety. In vitro studies (RBA) have shown that derivatives 9.1, 9.2, 9.4, 9.7, 9.9, 9.14 and 9.27 exhibit high affinity to molecular targets 5-HT1A receptor and SERT protein. In general, compounds with an unsubstituted or a para-substituted benzene ring of the pyrido[1,2-c]pyrimidine residue in the terminal part were characterized by higher binding ability, which can be justified by the greater flexibility of the structure. For the selected compounds 9.1, 9.7, 9.9 and 9.27, further in vitro, in vivo and metabolic stability tests were performed. The in vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) indicated their selectivity toward the 5-HT1A receptor and SERT protein. The in vivo studies (8-OH-DPAT-induced hypothermia in mice, FST) revealed that the compound 9.1 has the properties of presynaptic agonist of the 5-HT1A receptor, and compound 9.7 demonstrated the properties of a presynaptic antagonist of the 5-HT1A receptor. Metabolic stability studies, in turn, showed that compounds 9.1, 9.7 and 9.9, having an unsubstituted indole residue, were more resistant to biotransformation reactions of the first pass phase than was compound 9.27 containing a 5-methoxy-substituted indole residue. The obtained results allowed further optimization of the structure.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.63
%
|
|
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.
|
Binding affinity to SERT (unknown origin)
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis, crystal structure and biological activity of novel analogues of tricyclic drugs.
Year : 2020
Volume : 30
Issue : 21.0
First Page : 127493
Last Page : 127493
Authors : Bieszczad B,Siwek A,Wilczek M,Trzybiński D,Woźniak K,Satała G,Bojarski AJ,Mieczkowski A
Abstract : A series of fourteen novel, eight-membered lactam- and dilactam-based analogues of tricyclic drugs were obtained in a simple one-pot procedure. Crystal structures of two compounds were determined by single-crystal X-ray diffraction analysis and their selected structural features were discussed and compared with those of imipramine and dibenzepine. Affinity of developed molecules for histamine receptor H, serotonin receptors 5-HT, 5-HT, 5-HT, 5-HT, serotonin transporter (SERT) and dopamine receptor D was determined. The commercial drug dibenzepine was also checked on these molecular targets, as its mechanism of action is largely unknown. Two derivatives of 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one (7,8) and two of dibenzo[b,f]azocin-6(5H)-one (9,10) were found to be active toward the H receptor in sub-micromolar concentrations.
|
Binding affinity to H1 receptor (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis, crystal structure and biological activity of novel analogues of tricyclic drugs.
Year : 2020
Volume : 30
Issue : 21.0
First Page : 127493
Last Page : 127493
Authors : Bieszczad B,Siwek A,Wilczek M,Trzybiński D,Woźniak K,Satała G,Bojarski AJ,Mieczkowski A
Abstract : A series of fourteen novel, eight-membered lactam- and dilactam-based analogues of tricyclic drugs were obtained in a simple one-pot procedure. Crystal structures of two compounds were determined by single-crystal X-ray diffraction analysis and their selected structural features were discussed and compared with those of imipramine and dibenzepine. Affinity of developed molecules for histamine receptor H, serotonin receptors 5-HT, 5-HT, 5-HT, 5-HT, serotonin transporter (SERT) and dopamine receptor D was determined. The commercial drug dibenzepine was also checked on these molecular targets, as its mechanism of action is largely unknown. Two derivatives of 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one (7,8) and two of dibenzo[b,f]azocin-6(5H)-one (9,10) were found to be active toward the H receptor in sub-micromolar concentrations.
|
Displacement of [3H]-(+)-pentazocine from sigma 1 receptor in Sprague-Dawley rat brain membranes by scintillation counting method
|
Rattus norvegicus
|
343.0
nM
|
|
Journal : J Med Chem
Title : Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases.
Year : 2020
Volume : 63
Issue : 24.0
First Page : 15187
Last Page : 15217
Authors : Ye N,Qin W,Tian S,Xu Q,Wold EA,Zhou J,Zhen XC
Abstract : The sigma-1 (σ) receptor, an enigmatic protein originally classified as an opioid receptor subtype, is now understood to possess unique structural and functional features of its own and play critical roles to widely impact signaling transduction by interacting with receptors, ion channels, lipids, and kinases. The σ receptor is implicated in modulating learning, memory, emotion, sensory systems, neuronal development, and cognition and accordingly is now an actively pursued drug target for various neurological and neuropsychiatric disorders. Evaluation of the five selective σ receptor drug candidates (pridopidine, ANAVEX2-73, SA4503, S1RA, and T-817MA) that have entered clinical trials has shown that reaching clinical approval remains an evasive and important goal. This review provides up-to-date information on the selective targeting of σ receptors, including their history, function, reported crystal structures, and roles in neurological diseases, as well as a useful collation of new chemical entities as σ selective orthosteric ligands or allosteric modulators.
|
Inhibition of SERT (unknown origin)
|
Homo sapiens
|
29.0
nM
|
|
Journal : J Med Chem
Title : Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases.
Year : 2020
Volume : 63
Issue : 24.0
First Page : 15187
Last Page : 15217
Authors : Ye N,Qin W,Tian S,Xu Q,Wold EA,Zhou J,Zhen XC
Abstract : The sigma-1 (σ) receptor, an enigmatic protein originally classified as an opioid receptor subtype, is now understood to possess unique structural and functional features of its own and play critical roles to widely impact signaling transduction by interacting with receptors, ion channels, lipids, and kinases. The σ receptor is implicated in modulating learning, memory, emotion, sensory systems, neuronal development, and cognition and accordingly is now an actively pursued drug target for various neurological and neuropsychiatric disorders. Evaluation of the five selective σ receptor drug candidates (pridopidine, ANAVEX2-73, SA4503, S1RA, and T-817MA) that have entered clinical trials has shown that reaching clinical approval remains an evasive and important goal. This review provides up-to-date information on the selective targeting of σ receptors, including their history, function, reported crystal structures, and roles in neurological diseases, as well as a useful collation of new chemical entities as σ selective orthosteric ligands or allosteric modulators.
|
Displacement of SGRG-K(Ac)-GG-K(Ac)-GLG-K(Ac)-GGA-K(Ac)-RHRKVGG-K(Biotin) from Europium chelated human BRD4 bromodomain 1 (49 to 170 residues) measured after 2 hrs by TR-FRET assay
|
Homo sapiens
|
10.2
10^2 uM
|
|
|
Displacement of SGRG-K(Ac)-GG-K(Ac)-GLG-K(Ac)-GGA-K(Ac)-RHRKVGG-K(Biotin) from Europium chelated human BRD4 bromodomain 2 (342 to 460 residues) measured after 2 hrs by TR-FRET assay
|
Homo sapiens
|
6.47
10^2 uM
|
|
