|
The compound was tested for its binding affinity towards 5-hydroxytryptamine 1 receptor by displacing [3H]5-HT radioligand in rat cerebral cortex
|
None
|
842.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrole mannich bases as potential antipsychotic agents.
Year : 1992
Volume : 35
Issue : 3
First Page : 552
Last Page : 558
Authors : Scott MK, Martin GE, DiStefano DL, Fedde CL, Kukla MJ, Barrett DL, Baldy WJ, Elgin RJ, Kesslick JM, Mathiasen JR.
Abstract : Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.
|
Binding affinity at serotonin 5-hydroxytryptamine 2 receptor by [3H]ketanserin displacement.
|
None
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Development of a receptor-interaction model for serotonin 5-HT2 receptor antagonists. Predicting selectivity with respect to dopamine D2 receptors.
Year : 1994
Volume : 37
Issue : 7
First Page : 950
Last Page : 962
Authors : Andersen K, Liljefors T, Gundertofte K, Perregaard J, Bøgesø KP.
Abstract : A receptor-interaction model for serotonin 5-HT2 receptor antagonists has been developed by conformational analysis with molecular mechanics (MM2(91)) and superimposition studies of serotonin 5-HT2 receptor antagonists. Substituted 3-(4-piperidinyl)-,1-(4- piperidinyl)-,3-(1,2,3,6-tetrahydropyridin-4-yl)-, and 1-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles, substituted 3-(4-fluorophenyl)-1-(4-piperazinyl)indans, cyprohepatadine derivatives, ritanserin, and danitracene have been used as bases for the model. Other serotonin 5-HT2 receptor antagonists, such as ketanserin and MDL 11,939, are well accommodated into the model. Comparison of the model with a recently described receptor-interaction model for dopamine D2 receptor antagonists suggests a common pharmacophore for dopamine D2 and serotonin 5-HT2 receptor antagonists. Important steric differences between 5-HT2 receptor antagonists with additional high affinity for dopamine D2 receptors and serotonin 5-HT2 receptor antagonists with high selectivity versus D2 receptors are described. The geometry of the receptor-interaction model described is significantly different from that of a recently reported receptor-interaction model for 5-HT2 receptor agonists and antagonists developed by use of (+)-LSD as a template, suggesting the existence of two binding modes at the 5-HT2 receptor.
|
Compound was tested for the displacement of [3H]ketanserin from serotonin 5-hydroxytryptamine 2 receptor
|
None
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Selective, centrally acting serotonin 5-HT2 antagonists. 2. Substituted 3-(4-fluorophenyl)-1H-indoles.
Year : 1992
Volume : 35
Issue : 26
First Page : 4823
Last Page : 4831
Authors : Andersen K, Perregaard J, Arnt J, Nielsen JB, Begtrup M.
Abstract : A series of 3-(4-fluorophenyl)-1H-indoles substituted in the 1-position with 4-piperidinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperazinyl was synthesized. By variation of the substituents in the benzene part of the indole nucleus in 1-[2-[4-[3-4-fluorophenyl)-1H-indol-1-yl]-1-piperidinyl]-ethyl]-2- imidazolidinones, the highest 5-HT2 receptor affinity and selectivity with respect to dopamine D2 receptors and alpha 1 adrenoceptors were obtained by 5-methyl substitution. Different substituents were introduced in the 1-position of the piperidine ring in the 5-methyl-substituted derivative. Thus replacement of the 2-(2-imidazolidinon-1-yl)ethyl side chain with a 2-(1,3-dimethyl-1-ureido)ethyl or methyl substituent resulted in unchanged affinity and selectivity for 5-HT2 receptors. Replacement with a 2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl side chain reduced binding to alpha 1 adrenoceptors with a factor of four, while affinities for 5-HT2 and D2 receptors were retained, compared to the 3-unsubstituted imidazolidinone. Indoles substituted in the 1-position with 4-piperazinyl had generally weaker affinity for both 5-HT2 and D2 receptors compared to corresponding 4-piperidinyl- and 1,2,3,6-tetrahydro-4-pyridinyl-substituted indoles. Introduction of a methyl group in the 2-position of the 5-methyl-substituted indole resulted in further increase of selectivity for the 5-HT2 receptor. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and showed a long duration of action (> 24 h). In general, the derivatives were found to be considerably more potent at 24 h than at 2 h after the administration. The compounds within this series were prepared as analogues of the previously described 1-(4-fluorophenyl)-3-(4-piperidyl)-1H-indoles by interchange of the C-3 carbon atom and the nitrogen atom in the indole nucleus. The pharmacological results indicate that this isosteric replacement results in higher selectivity for 5-HT2 receptors compared to the former series. The 1-[2-[4-[2,5-dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl]-1- piperidinyl]ethyl]-2-imidazolidinone has high affinity for 5-HT2 receptors (IC50 = 3.4 nM) and extremely low affinity for both dopamine D2 receptors (IC50 = 6900 nM) and alpha 1 adrenoceptors (IC50 = 2300 nM).
|
Compound was tested for the displacement of [3H]ketanserin from serotonin 5-hydroxytryptamine 2 receptor from rat cortical membranes.
|
None
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Selective, centrally acting serotonin 5-HT2 antagonists. 1. 2- and 6-substituted 1-phenyl-3-(4-piperidinyl)-1H-indoles.
Year : 1992
Volume : 35
Issue : 26
First Page : 4813
Last Page : 4822
Authors : Perregaard J, Andersen K, Hyttel J, Sánchez C.
Abstract : A series of 1-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-imidazolidinones has been synthesized. The 1-position of the indole is substituted with phenyl groups and in the 2- or 6-positions are additional substituents. An analogous series with the imidazolidinone ring opened to corresponding urea derivatives was also prepared. High potency and selectivity for 5-HT2 receptors (as compared with D2 and alpha 1 receptor affinities) were obtained with medium-large substituents such as 6-chloro, 6-methyl, and 6-trifluoromethyl or a 2-methyl substituent. Larger 6-substituents such as isopropyl considerably reduced activity, while the smaller 6-fluoro substituent afforded unselective compounds. Selective 5-HT2 antagonists were found by combining 6-substitution with both unsubstituted 1-phenyl and substituted 1-phenyl groups (2-F, 4-F, 4-Cl). However, 3-substitution of the phenyl group markedly reduced 5-HT2 receptor affinity, especially with a 3-trifluoromethyl substituent. Introduction of a 3-(2-propyl) substituent in the imidazolidinone ring reduced binding to alpha 1 adrenoceptors with a factor of 3-8. Practically no influence on 5-HT2 and D2 receptor affinities were found by the presence of this substituent compared to the 3-unsubstituted derivatives. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and they had a long duration of action (> 24 h). Especially urea derivatives were found to be considerably more potent at 24 h than at 2 h after subcutaneous administration. Some of the compounds potently inhibited isolation-induced aggression in mice, an effect which, however, did not correlate to 5-HT2 receptor-mediated activities. On the basis of these structure-activity studies 1-[2-[4-[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1- piperidinyl]ethyl]-3-(2-propyl)-2-imidazolidinone (Lu 26-042, compound 4c) was selected for further pharmacological and toxicological investigations.
|
Inhibition of [3H]spiperone binding to 5-hydroxytryptamine 2 receptor from rat cortical membranes
|
None
|
4.4
nM
|
|
Journal : J. Med. Chem.
Title : Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity.
Year : 1988
Volume : 31
Issue : 12
First Page : 2247
Last Page : 2256
Authors : Bøgesø KP, Arnt J, Boeck V, Christensen AV, Hyttel J, Jensen KG.
Abstract : A series of trans-1-piperazino-3-phenylindans were synthesized with the goal of replacing their established neuroleptic profile with that of peripheral 5-hydroxytryptamine (5-HT2) antagonism. Compounds with an unsubstituted or fluoro-substituted 6-position in the indan ring, and which had a five- or six-membered heterocyclic ring attached by an ethylene chain to the piperazine ring, satisfied this objective. Some of the compounds had potent antihypertensive activity in conscious, spontaneously hypertensive rats (SHR). In pithed rats they antagonized the pressor effect induced by 5-HT in doses 100-1000 times lower than doses needed to antagonize the pressor effect of phenylephrine. The effect was stereoselective and associated with enantiomers with 1R,3S absolute configuration. 1S,3R enantiomers inhibited the uptake of dopamine and norepinephrine in vitro. The compound with the best antihypertensive activity was (+)-(1R,3S)-1-[2-[4-[3-(4-fluorophenyl)-1-indanyl]-1- piperazinyl]ethyl]-2-imidazolidinone (Lu 21-098, irindalone). Its pharmacological profile resembled that of the standard compound ketanserin. There was a close structural correspondence between ketanserin and irindalone in a conformation that we recently identified as a D-2 receptor-relevant configuration of its neuroleptic "parent" tefludazine. This suggests that the dopaminergic (D-2) and the serotonergic (5-HT2) pharmacophores are structurally closely related.
|
Displacement of [3H]ketanserin from 5-hydroxytryptamine 2 receptor in rat cortical membranes
|
None
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Stereospecific and selective 5-HT2 antagonism in a series of 5-substituted trans-1-piperazino-3-phenylindans.
Year : 1993
Volume : 36
Issue : 19
First Page : 2761
Last Page : 2770
Authors : Bøgesø KP, Arnt J, Hyttel J, Pedersen H.
Abstract : A study of the effect of aromatic substitution on 5-HT2, D2, and alpha 1 receptor affinity in a subseries of new and previously synthesized 1-piperazino-3-phenylindans indicated that high 5-HT2 selectivity could be obtained in 5-substituted derivatives. Accordingly, a series of 5-substituted derivatives was synthesized with the goal of obtaining stereospecific and selective, centrally acting 5-HT2 antagonists. This goal was fulfilled in 5-chloro- or 5-fluoro-substituted compounds with 2-(3-alkyl-2-oxoimidazolidin-1-yl)ethyl- or 2-(tetrahydro-2-oxo-1H-pyrimidin-1-yl)ethylpiperazine substituents, as well as in their imidazolidine-2-thione or pyrimidine-2-thione analogues. The most interesting derivatives were resolved either directly via diastereomeric salts or by syntheses from resolved starting materials. Optical purity was determined by a 1H NMR method, using the chiral shift reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol. The compound (-)-trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden++ +-1- yl]piperazin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone ((-)-20) had the overall best profile with a high stereoselectivity (eudismic ratio: 68) and a high selectivity versus D2 and alpha 1 receptors (affinity ratios 182 and 191, respectively). It had a potent central effect but was shorter-acting than the tetrahydropyrimidinone or thione derivatives ((-)-39, (+)-40, (-)-41, and (+)-42). The observed activities of the compounds are settled in perspective in relation to a recently proposed D2 receptor interaction model. While there are no indications so far that trans-1-piperazino-3-phenylindans interact with D2 and 5-HT2 receptors in different conformations, the present study shows important differences in aromatic substitution effects. Only 5-HT2 receptors are able to accommodate a 5-substituent in the indan benzene ring, thus allowing syntheses of highly selective compounds.
|
The concentration required to inhibit [3H]ketanserin binding to 5-hydroxytryptamine 2 receptor in rat brain membranes (in vitro)
|
None
|
1.7
nM
|
|
Journal : J. Med. Chem.
Title : Naphthosultam derivatives: a new class of potent and selective 5-HT2 antagonists.
Year : 1991
Volume : 34
Issue : 8
First Page : 2477
Last Page : 2483
Authors : Malleron JL, Comte MT, Gueremy C, Peyronel JF, Truchon A, Blanchard JC, Doble A, Piot O, Zundel JL, Huon C.
Abstract : A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.
|
In vivo inhibitory activity of 10 mg/kg compound in rats against elevation of BP caused by 5-HT (300 ug/kg, iv) through 5-HT2 receptor 1 hr after oral administration
|
None
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.
Year : 1992
Volume : 35
Issue : 1
First Page : 189
Last Page : 194
Authors : Watanabe Y, Usui H, Kobayashi S, Yoshiwara H, Shibano T, Tanaka T, Morishima Y, Yasuoka M, Kanao M.
Abstract : A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.
|
In vitro antagonistic activity against the contraction induced by 5-HT through 5-hydroxytryptamine 2 receptor in rat thoracic aortic strips
|
None
|
1.585
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.
Year : 1992
Volume : 35
Issue : 1
First Page : 189
Last Page : 194
Authors : Watanabe Y, Usui H, Kobayashi S, Yoshiwara H, Shibano T, Tanaka T, Morishima Y, Yasuoka M, Kanao M.
Abstract : A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.
|
Binding affinity against 5-hydroxytryptamine 2 receptor from rat cortical synaptosomal membrane using radioligand [3H]ketanserin.
|
None
|
0.82
nM
|
|
Journal : J. Med. Chem.
Title : Bridged gamma-carbolines and derivatives possessing selective and combined affinity for 5-HT2 and D2 receptors.
Year : 1993
Volume : 36
Issue : 10
First Page : 1488
Last Page : 1495
Authors : Mewshaw RE, Silverman LS, Mathew RM, Kaiser C, Sherrill RG, Cheng M, Tiffany CW, Karbon EW, Bailey MA, Borosky SA.
Abstract : A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles and 6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indoles was prepared. Structural modifications of the lead compound, 11-[4-(4-fluorobenzoyl)propyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (5, Ki = 0.82 nM vs [3H]ketanserin) enabled the identification of the functionality necessary for high affinity at serotonin 5-HT2 and dopamine D2 receptors in ligand binding studies. The indole ring, as well as the benzoyl or isosteric benzisoxazole moiety, were essential for high affinity. Variations of the length of the side chains resulted in ligands having either selective affinity for the 5-HT2 receptor or a combination of 5-HT2 and D2 affinity. In vivo binding studies were performed on selected members in this series. The most potent member, 2-fluoro-11-[4-(4-fluorobenzoyl)butyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (36) had an ED50 of < 1 mg/kg at the 5-HT2 and D2 receptors following oral administration.
|
Binding constant against 5-hydroxytryptamine 2 receptor (in vitro)
|
None
|
0.69
nM
|
|
Journal : J. Med. Chem.
Title : Naphthosultam derivatives: a new class of potent and selective 5-HT2 antagonists.
Year : 1991
Volume : 34
Issue : 8
First Page : 2477
Last Page : 2483
Authors : Malleron JL, Comte MT, Gueremy C, Peyronel JF, Truchon A, Blanchard JC, Doble A, Piot O, Zundel JL, Huon C.
Abstract : A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.
|
In vitro binding affinity towards 5-hydroxytryptamine 2 receptor in rat striatal membranes by [3H]ketanserin displacement.
|
None
|
0.61
nM
|
|
Journal : J. Med. Chem.
Title : Examination of the D2/5-HT2 affinity ratios of resolved 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles: an enantioselective approach toward the design of potential atypical antipsychotics.
Year : 1993
Volume : 36
Issue : 21
First Page : 3073
Last Page : 3076
Authors : Mewshaw RE, Abreu ME, Silverman LS, Mathew RM, Tiffany CW, Bailey MA, Karbon EW, Ferkany JW, Kaiser C.
Abstract : Enantiomers of several N-substituted 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles were obtained by the resolution of 2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole and 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole followed by N-alkylation. These, as well as the racemates, were evaluated for their affinity for the 5-HT2 and D2 receptors. Those compounds possessing the 7S,10R stereochemistry were consistently recognized by the 5-HT2 and D2 receptors as the eutomer. 2-Fluoro-11-[4-(4-fluorophenyl)-4-oxobutyl]-5,6,7,8,9,10-hexahydro-7S,10 R- iminocyclohept[b]indole [(7S,10R)-8] had the highest affinity for the 5-HT2 receptor (Ki = 0.80 nM), while its distomer (7R,10S)-8 was the most selective member of this class of bridged gamma-carbolines (D2/5-HT2 = 562). Incorporation of a benzoyl or isosteric benzisoxazole moiety tethered by a four-carbon spacer to a bridged gamma-carboline nucleus, possessing the 7S,10R absolute configuration, produced high affinity ligands for the 5-HT2 and D2 receptors.
|
The compound was tested for its binding affinity towards 5-hydroxytryptamine 2 receptor by displacing [3H]ketanserin radioligand in rat cerebral cortex
|
None
|
0.26
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrole mannich bases as potential antipsychotic agents.
Year : 1992
Volume : 35
Issue : 3
First Page : 552
Last Page : 558
Authors : Scott MK, Martin GE, DiStefano DL, Fedde CL, Kukla MJ, Barrett DL, Baldy WJ, Elgin RJ, Kesslick JM, Mathiasen JR.
Abstract : Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.
|
Binding affinity was evaluated in vitro by displacement of [3H]ketanserin from 5-hydroxytryptamine 2A receptor on rat cortical membrane
|
None
|
0.631
nM
|
|
Journal : J. Med. Chem.
Title : New 2-piperazinylbenzimidazole derivatives as 5-HT3 antagonists. Synthesis and pharmacological evaluation.
Year : 1997
Volume : 40
Issue : 4
First Page : 586
Last Page : 593
Authors : Orjales A, Mosquera R, Labeaga L, Rodes R.
Abstract : A series of 2-piperazinylbenzimidazole derivatives were prepared and evaluated as 5-HT3 receptor antagonists. Their 5-HT3 receptor affinities were evaluated by radioligand binding assays, and their abilities to inhibit the 5-HT-induced Bezold-Jarisch reflex in anesthetized rats were determined. Compound 7e (lerisetron, pKi = 9.2) exhibited higher affinity for the 5-HT3 receptor than did tropisetron and granisetron, while compound 7q (pKi = 7.5) had very low affinity for this receptor, showing that substitution on the N1 atom of the benzimidazole ring is essential for affinity and activity. The effect of substitution on the aromatic ring of benzimidazole by several substituents in different positions is also discussed. A strong correlation between the 5-HT3 antagonistic activity of the studied compounds and the position of substitution on the aromatic ring was established. Thus, while the 4-methoxy derivative 7m showed weak affinity for the 5-HT3 receptor (pKi = 6.7), the 7-methoxy derivative 7n exhibited the highest affinity (pKi = 9.4). Compounds 7e and 7n are now under further investigation as drugs for the treatment of nausea and emesis evoked by cancer chemotherapy and radiation.
|
Binding affinity to serotonin 5-hydroxytryptamine 2A receptors using a radioligand [3H]ketanserin binding assay in rat cortical membranes
|
None
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Serotonin 5-HT2 receptor, dopamine D2 receptor, and alpha 1 adrenoceptor antagonists. Conformationally flexible analogues of the atypical antipsychotic sertindole.
Year : 1996
Volume : 39
Issue : 19
First Page : 3723
Last Page : 3738
Authors : Andersen K, Liljefors T, Hyttel J, Perregaard J.
Abstract : Conformationally flexible analogues of the atypical antipsychotic sertindole (1-[2-[4-[5-chloro -1-(4-fluorophenyl)-1H-indol-3-yl]-4-piperidinyl]ethyl]-2-imidazolidi non e) were synthesized. Replacement of the 4-piperidinyl ring in sertindole by a 2-(methylamino)ethoxy group or a 2-(methylamino)ethyl group (e.g. 1-[2-[2-[5-chloro-1-(4-fluorophenyl)-1H -indol-3-yloxy]ethyl-methylamino]ethyl]-2-imidazolidinone and 1-[3-[[2-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl] -ethyl]methylamino]propyl]-2-imidazolidinone results in binding affinities for serotonin 5-HT2A and dopamine D2 receptors, as well as alpha 1 adrenoceptors, which are very similar to those of sertindole. (Methylamino)alkyl groups of other chain lengths, 3-(methylamino)propyloxy groups, and 2-(methylamino)ethylsulfanyl groups do not have such properties. The capability of the 2-(methylamino)ethoxy group and the 2-(methylamino)ethyl group to replace the 4-piperidinyl ring in sertindole is reflected in molecular modeling studies using recently published receptor-interaction models for 5-HT2 and D2 receptors. Structure-affinity investigations concerning the substituents in the indole nucleus and the 2-imidazolidinone ring system in the 2-(methylamino)ethoxy and the 2-(methylamino)ethyl analogues of sertindole have led to high affinity serotonin 5-HT2A receptor antagonists with selectivity versus dopamine D2 receptors and alpha 1 adrenoceptors (e.g. 1-[2-[[2-[6-chloro-1-(4-fluorophenyl) -1H-indol-3-yloxy]ethyl]methylamino]-ethyl]-2-imidazolidinone and 1-[3-[[2-[6-chloro-1-(4-fluorophenyl) -1H-indol-3-yl]ethyl]methylamino]propyl]-2-imidazolidinone). The latter derivative has also high selectivity for 5-HT2A receptors versus serotonin 5-HT2C receptors. Replacement of the basic amino group by nitrogen-containing six-membered rings has led to 5-chloro-1-(4-fluorophenyl)-3-[(4-methylpiperazinyl)-ethoxy]-1H-in dole, which has high affinity for dopamine D2, versus low affinity for serotonin 5-HT2A receptors and alpha 1 adrenoceptors.
|
Binding affinity towards human 5-hydroxytryptamine 7 receptor
|
Homo sapiens
|
45.0
nM
|
|
Journal : J. Med. Chem.
Title : Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7).
Year : 2003
Volume : 46
Issue : 14
First Page : 2795
Last Page : 2812
Authors : Glennon RA.
|
Binding affinity towards rat 5-hydroxytryptamine 7 receptor
|
None
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7).
Year : 2003
Volume : 46
Issue : 14
First Page : 2795
Last Page : 2812
Authors : Glennon RA.
|
Binding affinity towards 5-hydroxytryptamine 7 receptor
|
None
|
15.85
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : First pharmacophoric hypothesis for 5-HT7 antagonism.
Year : 2000
Volume : 10
Issue : 10
First Page : 1097
Last Page : 1100
Authors : López-Rodríguez ML, Porras E, Benhamú B, Ramos JA, Morcillo MJ, Lavandera JL.
Abstract : In order to make the first contribution to the elucidation of essential structural features for 5-HT7 antagonism, a set of thirty 5-HT7 antagonists were selected from the literature. A pharmacophore model was built using Molecular Modeling studies with Catalyst program. The information contained in this model was validated with new synthesized compounds.
|
Non-selective inhibitory activity was determined against 5-hydroxytryptamine 7 receptor
|
None
|
15.85
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of the pharmacophore model for 5-HT7R antagonism. Design and synthesis of new naphtholactam and naphthosultam derivatives.
Year : 2003
Volume : 46
Issue : 26
First Page : 5638
Last Page : 5650
Authors : López-Rodríguez ML, Porras E, Morcillo MJ, Benhamú B, Soto LJ, Lavandera JL, Ramos JA, Olivella M, Campillo M, Pardo L.
Abstract : We present in this study an optimization of a preliminary pharmacophore model for 5-HT(7)R antagonism, with the incorporation of recently reported ligands and using an efficient procedure with the CATALYST program. The model consists of five features: a positive ionizable atom (PI), a H-bonding acceptor group (HBA), and three hydrophobic regions (HYD). This model has been supported by the design, synthesis, and biological evaluation of new naphtholactam and naphthosultam derivatives of general structure I (39-72). A systematic structure-affinity relationship (SAFIR) study on these analogues has allowed us to confirm that the model incorporates the essential structural features for 5-HT(7)R antagonism. In addition, computational simulation of the complex between compound 56 and a rhodopsin-based 3D model of the 5-HT(7)R transmembrane domain has permitted us to define the molecular details of the ligand-receptor interaction and gives additional support to the proposed pharmacophore model for 5-HT(7)R antagonism: (i) the HBA feature of the pharmacophore model binds Ser(5.42) and Thr(5.43), (ii) the HYD1 feature interacts with Phe(6.52), (iii) the PI feature forms an ionic interaction with Asp(3.32), and (iv) the HYD3 (AR) feature interacts with a set of aromatic residues (Phe(3.28), Tyr(7.43)). These results provide the tools for the design and synthesis of new ligands with predetermined affinities and pharmacological properties.
|
Displacement of [3H]prazosin from alpha-1 adrenoceptors in whole rat brain membranes
|
None
|
47.0
nM
|
|
Journal : J. Med. Chem.
Title : Stereospecific and selective 5-HT2 antagonism in a series of 5-substituted trans-1-piperazino-3-phenylindans.
Year : 1993
Volume : 36
Issue : 19
First Page : 2761
Last Page : 2770
Authors : Bøgesø KP, Arnt J, Hyttel J, Pedersen H.
Abstract : A study of the effect of aromatic substitution on 5-HT2, D2, and alpha 1 receptor affinity in a subseries of new and previously synthesized 1-piperazino-3-phenylindans indicated that high 5-HT2 selectivity could be obtained in 5-substituted derivatives. Accordingly, a series of 5-substituted derivatives was synthesized with the goal of obtaining stereospecific and selective, centrally acting 5-HT2 antagonists. This goal was fulfilled in 5-chloro- or 5-fluoro-substituted compounds with 2-(3-alkyl-2-oxoimidazolidin-1-yl)ethyl- or 2-(tetrahydro-2-oxo-1H-pyrimidin-1-yl)ethylpiperazine substituents, as well as in their imidazolidine-2-thione or pyrimidine-2-thione analogues. The most interesting derivatives were resolved either directly via diastereomeric salts or by syntheses from resolved starting materials. Optical purity was determined by a 1H NMR method, using the chiral shift reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol. The compound (-)-trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden++ +-1- yl]piperazin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone ((-)-20) had the overall best profile with a high stereoselectivity (eudismic ratio: 68) and a high selectivity versus D2 and alpha 1 receptors (affinity ratios 182 and 191, respectively). It had a potent central effect but was shorter-acting than the tetrahydropyrimidinone or thione derivatives ((-)-39, (+)-40, (-)-41, and (+)-42). The observed activities of the compounds are settled in perspective in relation to a recently proposed D2 receptor interaction model. While there are no indications so far that trans-1-piperazino-3-phenylindans interact with D2 and 5-HT2 receptors in different conformations, the present study shows important differences in aromatic substitution effects. Only 5-HT2 receptors are able to accommodate a 5-substituent in the indan benzene ring, thus allowing syntheses of highly selective compounds.
|
The compound was tested for its binding affinity towards Alpha-1 adrenergic receptor by displacing [3H]WB-4101 radioligand in rat cerebral cortex
|
None
|
49.5
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrole mannich bases as potential antipsychotic agents.
Year : 1992
Volume : 35
Issue : 3
First Page : 552
Last Page : 558
Authors : Scott MK, Martin GE, DiStefano DL, Fedde CL, Kukla MJ, Barrett DL, Baldy WJ, Elgin RJ, Kesslick JM, Mathiasen JR.
Abstract : Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.
|
In vivo inhibitory activity in rats against elevation of blood pressure caused by phenylephrine (30 ug/kg, iv) through Alpha-1 adrenergic receptor, after 1 hr oral administration at dose of 10 mg/kg
|
None
|
7.0
%
|
|
Journal : J. Med. Chem.
Title : Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.
Year : 1992
Volume : 35
Issue : 1
First Page : 189
Last Page : 194
Authors : Watanabe Y, Usui H, Kobayashi S, Yoshiwara H, Shibano T, Tanaka T, Morishima Y, Yasuoka M, Kanao M.
Abstract : A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.
|
In vitro antagonistic activity tested against the contraction induced by phenylephrine through Alpha-1 adrenergic receptor in rat thoracic aortic strips
|
None
|
31.62
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.
Year : 1992
Volume : 35
Issue : 1
First Page : 189
Last Page : 194
Authors : Watanabe Y, Usui H, Kobayashi S, Yoshiwara H, Shibano T, Tanaka T, Morishima Y, Yasuoka M, Kanao M.
Abstract : A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.
|
Binding affinity to the alpha-1 adrenergic receptor using a radioligand [3H]prazosin binding assay in rat brain membranes
|
None
|
47.0
nM
|
|
Journal : J. Med. Chem.
Title : Serotonin 5-HT2 receptor, dopamine D2 receptor, and alpha 1 adrenoceptor antagonists. Conformationally flexible analogues of the atypical antipsychotic sertindole.
Year : 1996
Volume : 39
Issue : 19
First Page : 3723
Last Page : 3738
Authors : Andersen K, Liljefors T, Hyttel J, Perregaard J.
Abstract : Conformationally flexible analogues of the atypical antipsychotic sertindole (1-[2-[4-[5-chloro -1-(4-fluorophenyl)-1H-indol-3-yl]-4-piperidinyl]ethyl]-2-imidazolidi non e) were synthesized. Replacement of the 4-piperidinyl ring in sertindole by a 2-(methylamino)ethoxy group or a 2-(methylamino)ethyl group (e.g. 1-[2-[2-[5-chloro-1-(4-fluorophenyl)-1H -indol-3-yloxy]ethyl-methylamino]ethyl]-2-imidazolidinone and 1-[3-[[2-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl] -ethyl]methylamino]propyl]-2-imidazolidinone results in binding affinities for serotonin 5-HT2A and dopamine D2 receptors, as well as alpha 1 adrenoceptors, which are very similar to those of sertindole. (Methylamino)alkyl groups of other chain lengths, 3-(methylamino)propyloxy groups, and 2-(methylamino)ethylsulfanyl groups do not have such properties. The capability of the 2-(methylamino)ethoxy group and the 2-(methylamino)ethyl group to replace the 4-piperidinyl ring in sertindole is reflected in molecular modeling studies using recently published receptor-interaction models for 5-HT2 and D2 receptors. Structure-affinity investigations concerning the substituents in the indole nucleus and the 2-imidazolidinone ring system in the 2-(methylamino)ethoxy and the 2-(methylamino)ethyl analogues of sertindole have led to high affinity serotonin 5-HT2A receptor antagonists with selectivity versus dopamine D2 receptors and alpha 1 adrenoceptors (e.g. 1-[2-[[2-[6-chloro-1-(4-fluorophenyl) -1H-indol-3-yloxy]ethyl]methylamino]-ethyl]-2-imidazolidinone and 1-[3-[[2-[6-chloro-1-(4-fluorophenyl) -1H-indol-3-yl]ethyl]methylamino]propyl]-2-imidazolidinone). The latter derivative has also high selectivity for 5-HT2A receptors versus serotonin 5-HT2C receptors. Replacement of the basic amino group by nitrogen-containing six-membered rings has led to 5-chloro-1-(4-fluorophenyl)-3-[(4-methylpiperazinyl)-ethoxy]-1H-in dole, which has high affinity for dopamine D2, versus low affinity for serotonin 5-HT2A receptors and alpha 1 adrenoceptors.
|
Compound was tested for i the displacement of [3H]prazosin from alpha-1 adrenergic receptor
|
None
|
47.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective, centrally acting serotonin 5-HT2 antagonists. 2. Substituted 3-(4-fluorophenyl)-1H-indoles.
Year : 1992
Volume : 35
Issue : 26
First Page : 4823
Last Page : 4831
Authors : Andersen K, Perregaard J, Arnt J, Nielsen JB, Begtrup M.
Abstract : A series of 3-(4-fluorophenyl)-1H-indoles substituted in the 1-position with 4-piperidinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperazinyl was synthesized. By variation of the substituents in the benzene part of the indole nucleus in 1-[2-[4-[3-4-fluorophenyl)-1H-indol-1-yl]-1-piperidinyl]-ethyl]-2- imidazolidinones, the highest 5-HT2 receptor affinity and selectivity with respect to dopamine D2 receptors and alpha 1 adrenoceptors were obtained by 5-methyl substitution. Different substituents were introduced in the 1-position of the piperidine ring in the 5-methyl-substituted derivative. Thus replacement of the 2-(2-imidazolidinon-1-yl)ethyl side chain with a 2-(1,3-dimethyl-1-ureido)ethyl or methyl substituent resulted in unchanged affinity and selectivity for 5-HT2 receptors. Replacement with a 2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl side chain reduced binding to alpha 1 adrenoceptors with a factor of four, while affinities for 5-HT2 and D2 receptors were retained, compared to the 3-unsubstituted imidazolidinone. Indoles substituted in the 1-position with 4-piperazinyl had generally weaker affinity for both 5-HT2 and D2 receptors compared to corresponding 4-piperidinyl- and 1,2,3,6-tetrahydro-4-pyridinyl-substituted indoles. Introduction of a methyl group in the 2-position of the 5-methyl-substituted indole resulted in further increase of selectivity for the 5-HT2 receptor. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and showed a long duration of action (> 24 h). In general, the derivatives were found to be considerably more potent at 24 h than at 2 h after the administration. The compounds within this series were prepared as analogues of the previously described 1-(4-fluorophenyl)-3-(4-piperidyl)-1H-indoles by interchange of the C-3 carbon atom and the nitrogen atom in the indole nucleus. The pharmacological results indicate that this isosteric replacement results in higher selectivity for 5-HT2 receptors compared to the former series. The 1-[2-[4-[2,5-dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl]-1- piperidinyl]ethyl]-2-imidazolidinone has high affinity for 5-HT2 receptors (IC50 = 3.4 nM) and extremely low affinity for both dopamine D2 receptors (IC50 = 6900 nM) and alpha 1 adrenoceptors (IC50 = 2300 nM).
|
Compound was tested for the displacement of [3H]prazosin from alpha-1 adrenergic receptor of rat striatal membranes
|
None
|
47.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective, centrally acting serotonin 5-HT2 antagonists. 1. 2- and 6-substituted 1-phenyl-3-(4-piperidinyl)-1H-indoles.
Year : 1992
Volume : 35
Issue : 26
First Page : 4813
Last Page : 4822
Authors : Perregaard J, Andersen K, Hyttel J, Sánchez C.
Abstract : A series of 1-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-imidazolidinones has been synthesized. The 1-position of the indole is substituted with phenyl groups and in the 2- or 6-positions are additional substituents. An analogous series with the imidazolidinone ring opened to corresponding urea derivatives was also prepared. High potency and selectivity for 5-HT2 receptors (as compared with D2 and alpha 1 receptor affinities) were obtained with medium-large substituents such as 6-chloro, 6-methyl, and 6-trifluoromethyl or a 2-methyl substituent. Larger 6-substituents such as isopropyl considerably reduced activity, while the smaller 6-fluoro substituent afforded unselective compounds. Selective 5-HT2 antagonists were found by combining 6-substitution with both unsubstituted 1-phenyl and substituted 1-phenyl groups (2-F, 4-F, 4-Cl). However, 3-substitution of the phenyl group markedly reduced 5-HT2 receptor affinity, especially with a 3-trifluoromethyl substituent. Introduction of a 3-(2-propyl) substituent in the imidazolidinone ring reduced binding to alpha 1 adrenoceptors with a factor of 3-8. Practically no influence on 5-HT2 and D2 receptor affinities were found by the presence of this substituent compared to the 3-unsubstituted derivatives. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and they had a long duration of action (> 24 h). Especially urea derivatives were found to be considerably more potent at 24 h than at 2 h after subcutaneous administration. Some of the compounds potently inhibited isolation-induced aggression in mice, an effect which, however, did not correlate to 5-HT2 receptor-mediated activities. On the basis of these structure-activity studies 1-[2-[4-[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1- piperidinyl]ethyl]-3-(2-propyl)-2-imidazolidinone (Lu 26-042, compound 4c) was selected for further pharmacological and toxicological investigations.
|
Inhibition of [3H]prazosin binding to alpha-1 adrenergic receptor from rat cortical membranes
|
None
|
47.0
nM
|
|
Journal : J. Med. Chem.
Title : Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity.
Year : 1988
Volume : 31
Issue : 12
First Page : 2247
Last Page : 2256
Authors : Bøgesø KP, Arnt J, Boeck V, Christensen AV, Hyttel J, Jensen KG.
Abstract : A series of trans-1-piperazino-3-phenylindans were synthesized with the goal of replacing their established neuroleptic profile with that of peripheral 5-hydroxytryptamine (5-HT2) antagonism. Compounds with an unsubstituted or fluoro-substituted 6-position in the indan ring, and which had a five- or six-membered heterocyclic ring attached by an ethylene chain to the piperazine ring, satisfied this objective. Some of the compounds had potent antihypertensive activity in conscious, spontaneously hypertensive rats (SHR). In pithed rats they antagonized the pressor effect induced by 5-HT in doses 100-1000 times lower than doses needed to antagonize the pressor effect of phenylephrine. The effect was stereoselective and associated with enantiomers with 1R,3S absolute configuration. 1S,3R enantiomers inhibited the uptake of dopamine and norepinephrine in vitro. The compound with the best antihypertensive activity was (+)-(1R,3S)-1-[2-[4-[3-(4-fluorophenyl)-1-indanyl]-1- piperazinyl]ethyl]-2-imidazolidinone (Lu 21-098, irindalone). Its pharmacological profile resembled that of the standard compound ketanserin. There was a close structural correspondence between ketanserin and irindalone in a conformation that we recently identified as a D-2 receptor-relevant configuration of its neuroleptic "parent" tefludazine. This suggests that the dopaminergic (D-2) and the serotonergic (5-HT2) pharmacophores are structurally closely related.
|
The concentration required to inhibit [3H]prazosin binding to Alpha-1 adrenergic receptor in rat brain membranes was measured (in vitro)
|
None
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : Naphthosultam derivatives: a new class of potent and selective 5-HT2 antagonists.
Year : 1991
Volume : 34
Issue : 8
First Page : 2477
Last Page : 2483
Authors : Malleron JL, Comte MT, Gueremy C, Peyronel JF, Truchon A, Blanchard JC, Doble A, Piot O, Zundel JL, Huon C.
Abstract : A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.
|
Binding constant against Alpha-1 adrenergic receptor (in vitro)
|
None
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Naphthosultam derivatives: a new class of potent and selective 5-HT2 antagonists.
Year : 1991
Volume : 34
Issue : 8
First Page : 2477
Last Page : 2483
Authors : Malleron JL, Comte MT, Gueremy C, Peyronel JF, Truchon A, Blanchard JC, Doble A, Piot O, Zundel JL, Huon C.
Abstract : A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.
|
Binding affinity to dopamine receptor D2 using a [3H]-spiperone binding assay in rat cortical membranes
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Serotonin 5-HT2 receptor, dopamine D2 receptor, and alpha 1 adrenoceptor antagonists. Conformationally flexible analogues of the atypical antipsychotic sertindole.
Year : 1996
Volume : 39
Issue : 19
First Page : 3723
Last Page : 3738
Authors : Andersen K, Liljefors T, Hyttel J, Perregaard J.
Abstract : Conformationally flexible analogues of the atypical antipsychotic sertindole (1-[2-[4-[5-chloro -1-(4-fluorophenyl)-1H-indol-3-yl]-4-piperidinyl]ethyl]-2-imidazolidi non e) were synthesized. Replacement of the 4-piperidinyl ring in sertindole by a 2-(methylamino)ethoxy group or a 2-(methylamino)ethyl group (e.g. 1-[2-[2-[5-chloro-1-(4-fluorophenyl)-1H -indol-3-yloxy]ethyl-methylamino]ethyl]-2-imidazolidinone and 1-[3-[[2-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl] -ethyl]methylamino]propyl]-2-imidazolidinone results in binding affinities for serotonin 5-HT2A and dopamine D2 receptors, as well as alpha 1 adrenoceptors, which are very similar to those of sertindole. (Methylamino)alkyl groups of other chain lengths, 3-(methylamino)propyloxy groups, and 2-(methylamino)ethylsulfanyl groups do not have such properties. The capability of the 2-(methylamino)ethoxy group and the 2-(methylamino)ethyl group to replace the 4-piperidinyl ring in sertindole is reflected in molecular modeling studies using recently published receptor-interaction models for 5-HT2 and D2 receptors. Structure-affinity investigations concerning the substituents in the indole nucleus and the 2-imidazolidinone ring system in the 2-(methylamino)ethoxy and the 2-(methylamino)ethyl analogues of sertindole have led to high affinity serotonin 5-HT2A receptor antagonists with selectivity versus dopamine D2 receptors and alpha 1 adrenoceptors (e.g. 1-[2-[[2-[6-chloro-1-(4-fluorophenyl) -1H-indol-3-yloxy]ethyl]methylamino]-ethyl]-2-imidazolidinone and 1-[3-[[2-[6-chloro-1-(4-fluorophenyl) -1H-indol-3-yl]ethyl]methylamino]propyl]-2-imidazolidinone). The latter derivative has also high selectivity for 5-HT2A receptors versus serotonin 5-HT2C receptors. Replacement of the basic amino group by nitrogen-containing six-membered rings has led to 5-chloro-1-(4-fluorophenyl)-3-[(4-methylpiperazinyl)-ethoxy]-1H-in dole, which has high affinity for dopamine D2, versus low affinity for serotonin 5-HT2A receptors and alpha 1 adrenoceptors.
|
Binding affinity at dopamine D2 receptor by [3H]spiperone displacement.
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a receptor-interaction model for serotonin 5-HT2 receptor antagonists. Predicting selectivity with respect to dopamine D2 receptors.
Year : 1994
Volume : 37
Issue : 7
First Page : 950
Last Page : 962
Authors : Andersen K, Liljefors T, Gundertofte K, Perregaard J, Bøgesø KP.
Abstract : A receptor-interaction model for serotonin 5-HT2 receptor antagonists has been developed by conformational analysis with molecular mechanics (MM2(91)) and superimposition studies of serotonin 5-HT2 receptor antagonists. Substituted 3-(4-piperidinyl)-,1-(4- piperidinyl)-,3-(1,2,3,6-tetrahydropyridin-4-yl)-, and 1-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles, substituted 3-(4-fluorophenyl)-1-(4-piperazinyl)indans, cyprohepatadine derivatives, ritanserin, and danitracene have been used as bases for the model. Other serotonin 5-HT2 receptor antagonists, such as ketanserin and MDL 11,939, are well accommodated into the model. Comparison of the model with a recently described receptor-interaction model for dopamine D2 receptor antagonists suggests a common pharmacophore for dopamine D2 and serotonin 5-HT2 receptor antagonists. Important steric differences between 5-HT2 receptor antagonists with additional high affinity for dopamine D2 receptors and serotonin 5-HT2 receptor antagonists with high selectivity versus D2 receptors are described. The geometry of the receptor-interaction model described is significantly different from that of a recently reported receptor-interaction model for 5-HT2 receptor agonists and antagonists developed by use of (+)-LSD as a template, suggesting the existence of two binding modes at the 5-HT2 receptor.
|
Compound was tested for the displacement of [3H]spiperone from dopamine receptor D2
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective, centrally acting serotonin 5-HT2 antagonists. 2. Substituted 3-(4-fluorophenyl)-1H-indoles.
Year : 1992
Volume : 35
Issue : 26
First Page : 4823
Last Page : 4831
Authors : Andersen K, Perregaard J, Arnt J, Nielsen JB, Begtrup M.
Abstract : A series of 3-(4-fluorophenyl)-1H-indoles substituted in the 1-position with 4-piperidinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperazinyl was synthesized. By variation of the substituents in the benzene part of the indole nucleus in 1-[2-[4-[3-4-fluorophenyl)-1H-indol-1-yl]-1-piperidinyl]-ethyl]-2- imidazolidinones, the highest 5-HT2 receptor affinity and selectivity with respect to dopamine D2 receptors and alpha 1 adrenoceptors were obtained by 5-methyl substitution. Different substituents were introduced in the 1-position of the piperidine ring in the 5-methyl-substituted derivative. Thus replacement of the 2-(2-imidazolidinon-1-yl)ethyl side chain with a 2-(1,3-dimethyl-1-ureido)ethyl or methyl substituent resulted in unchanged affinity and selectivity for 5-HT2 receptors. Replacement with a 2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl side chain reduced binding to alpha 1 adrenoceptors with a factor of four, while affinities for 5-HT2 and D2 receptors were retained, compared to the 3-unsubstituted imidazolidinone. Indoles substituted in the 1-position with 4-piperazinyl had generally weaker affinity for both 5-HT2 and D2 receptors compared to corresponding 4-piperidinyl- and 1,2,3,6-tetrahydro-4-pyridinyl-substituted indoles. Introduction of a methyl group in the 2-position of the 5-methyl-substituted indole resulted in further increase of selectivity for the 5-HT2 receptor. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and showed a long duration of action (> 24 h). In general, the derivatives were found to be considerably more potent at 24 h than at 2 h after the administration. The compounds within this series were prepared as analogues of the previously described 1-(4-fluorophenyl)-3-(4-piperidyl)-1H-indoles by interchange of the C-3 carbon atom and the nitrogen atom in the indole nucleus. The pharmacological results indicate that this isosteric replacement results in higher selectivity for 5-HT2 receptors compared to the former series. The 1-[2-[4-[2,5-dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl]-1- piperidinyl]ethyl]-2-imidazolidinone has high affinity for 5-HT2 receptors (IC50 = 3.4 nM) and extremely low affinity for both dopamine D2 receptors (IC50 = 6900 nM) and alpha 1 adrenoceptors (IC50 = 2300 nM).
|
Compound was tested for the displacement of [3H]spiperone from dopamine receptor D2 from rat striatal membranes.
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective, centrally acting serotonin 5-HT2 antagonists. 1. 2- and 6-substituted 1-phenyl-3-(4-piperidinyl)-1H-indoles.
Year : 1992
Volume : 35
Issue : 26
First Page : 4813
Last Page : 4822
Authors : Perregaard J, Andersen K, Hyttel J, Sánchez C.
Abstract : A series of 1-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-imidazolidinones has been synthesized. The 1-position of the indole is substituted with phenyl groups and in the 2- or 6-positions are additional substituents. An analogous series with the imidazolidinone ring opened to corresponding urea derivatives was also prepared. High potency and selectivity for 5-HT2 receptors (as compared with D2 and alpha 1 receptor affinities) were obtained with medium-large substituents such as 6-chloro, 6-methyl, and 6-trifluoromethyl or a 2-methyl substituent. Larger 6-substituents such as isopropyl considerably reduced activity, while the smaller 6-fluoro substituent afforded unselective compounds. Selective 5-HT2 antagonists were found by combining 6-substitution with both unsubstituted 1-phenyl and substituted 1-phenyl groups (2-F, 4-F, 4-Cl). However, 3-substitution of the phenyl group markedly reduced 5-HT2 receptor affinity, especially with a 3-trifluoromethyl substituent. Introduction of a 3-(2-propyl) substituent in the imidazolidinone ring reduced binding to alpha 1 adrenoceptors with a factor of 3-8. Practically no influence on 5-HT2 and D2 receptor affinities were found by the presence of this substituent compared to the 3-unsubstituted derivatives. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and they had a long duration of action (> 24 h). Especially urea derivatives were found to be considerably more potent at 24 h than at 2 h after subcutaneous administration. Some of the compounds potently inhibited isolation-induced aggression in mice, an effect which, however, did not correlate to 5-HT2 receptor-mediated activities. On the basis of these structure-activity studies 1-[2-[4-[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1- piperidinyl]ethyl]-3-(2-propyl)-2-imidazolidinone (Lu 26-042, compound 4c) was selected for further pharmacological and toxicological investigations.
|
Inhibition of [3H]spiperone binding to Dopamine receptor D2 from rat striatal membranes
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity.
Year : 1988
Volume : 31
Issue : 12
First Page : 2247
Last Page : 2256
Authors : Bøgesø KP, Arnt J, Boeck V, Christensen AV, Hyttel J, Jensen KG.
Abstract : A series of trans-1-piperazino-3-phenylindans were synthesized with the goal of replacing their established neuroleptic profile with that of peripheral 5-hydroxytryptamine (5-HT2) antagonism. Compounds with an unsubstituted or fluoro-substituted 6-position in the indan ring, and which had a five- or six-membered heterocyclic ring attached by an ethylene chain to the piperazine ring, satisfied this objective. Some of the compounds had potent antihypertensive activity in conscious, spontaneously hypertensive rats (SHR). In pithed rats they antagonized the pressor effect induced by 5-HT in doses 100-1000 times lower than doses needed to antagonize the pressor effect of phenylephrine. The effect was stereoselective and associated with enantiomers with 1R,3S absolute configuration. 1S,3R enantiomers inhibited the uptake of dopamine and norepinephrine in vitro. The compound with the best antihypertensive activity was (+)-(1R,3S)-1-[2-[4-[3-(4-fluorophenyl)-1-indanyl]-1- piperazinyl]ethyl]-2-imidazolidinone (Lu 21-098, irindalone). Its pharmacological profile resembled that of the standard compound ketanserin. There was a close structural correspondence between ketanserin and irindalone in a conformation that we recently identified as a D-2 receptor-relevant configuration of its neuroleptic "parent" tefludazine. This suggests that the dopaminergic (D-2) and the serotonergic (5-HT2) pharmacophores are structurally closely related.
|
Displacement of [3H]spiperone from dopamine D2 receptors in rat striatal membranes
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Stereospecific and selective 5-HT2 antagonism in a series of 5-substituted trans-1-piperazino-3-phenylindans.
Year : 1993
Volume : 36
Issue : 19
First Page : 2761
Last Page : 2770
Authors : Bøgesø KP, Arnt J, Hyttel J, Pedersen H.
Abstract : A study of the effect of aromatic substitution on 5-HT2, D2, and alpha 1 receptor affinity in a subseries of new and previously synthesized 1-piperazino-3-phenylindans indicated that high 5-HT2 selectivity could be obtained in 5-substituted derivatives. Accordingly, a series of 5-substituted derivatives was synthesized with the goal of obtaining stereospecific and selective, centrally acting 5-HT2 antagonists. This goal was fulfilled in 5-chloro- or 5-fluoro-substituted compounds with 2-(3-alkyl-2-oxoimidazolidin-1-yl)ethyl- or 2-(tetrahydro-2-oxo-1H-pyrimidin-1-yl)ethylpiperazine substituents, as well as in their imidazolidine-2-thione or pyrimidine-2-thione analogues. The most interesting derivatives were resolved either directly via diastereomeric salts or by syntheses from resolved starting materials. Optical purity was determined by a 1H NMR method, using the chiral shift reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol. The compound (-)-trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden++ +-1- yl]piperazin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone ((-)-20) had the overall best profile with a high stereoselectivity (eudismic ratio: 68) and a high selectivity versus D2 and alpha 1 receptors (affinity ratios 182 and 191, respectively). It had a potent central effect but was shorter-acting than the tetrahydropyrimidinone or thione derivatives ((-)-39, (+)-40, (-)-41, and (+)-42). The observed activities of the compounds are settled in perspective in relation to a recently proposed D2 receptor interaction model. While there are no indications so far that trans-1-piperazino-3-phenylindans interact with D2 and 5-HT2 receptors in different conformations, the present study shows important differences in aromatic substitution effects. Only 5-HT2 receptors are able to accommodate a 5-substituent in the indan benzene ring, thus allowing syntheses of highly selective compounds.
|
The concentration required to inhibit [3H]spiperone binding to dopamine receptor D2 in rat brain membranes (in vitro)
|
None
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Naphthosultam derivatives: a new class of potent and selective 5-HT2 antagonists.
Year : 1991
Volume : 34
Issue : 8
First Page : 2477
Last Page : 2483
Authors : Malleron JL, Comte MT, Gueremy C, Peyronel JF, Truchon A, Blanchard JC, Doble A, Piot O, Zundel JL, Huon C.
Abstract : A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.
|
Binding affinity against dopamine receptor D2 from rat corpus striatum by using radioligand [3H]sulpiride
|
None
|
93.0
nM
|
|
Journal : J. Med. Chem.
Title : Bridged gamma-carbolines and derivatives possessing selective and combined affinity for 5-HT2 and D2 receptors.
Year : 1993
Volume : 36
Issue : 10
First Page : 1488
Last Page : 1495
Authors : Mewshaw RE, Silverman LS, Mathew RM, Kaiser C, Sherrill RG, Cheng M, Tiffany CW, Karbon EW, Bailey MA, Borosky SA.
Abstract : A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles and 6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indoles was prepared. Structural modifications of the lead compound, 11-[4-(4-fluorobenzoyl)propyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (5, Ki = 0.82 nM vs [3H]ketanserin) enabled the identification of the functionality necessary for high affinity at serotonin 5-HT2 and dopamine D2 receptors in ligand binding studies. The indole ring, as well as the benzoyl or isosteric benzisoxazole moiety, were essential for high affinity. Variations of the length of the side chains resulted in ligands having either selective affinity for the 5-HT2 receptor or a combination of 5-HT2 and D2 affinity. In vivo binding studies were performed on selected members in this series. The most potent member, 2-fluoro-11-[4-(4-fluorobenzoyl)butyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (36) had an ED50 of < 1 mg/kg at the 5-HT2 and D2 receptors following oral administration.
|
Binding constant against dopamine receptor D2 (in vitro)
|
None
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Naphthosultam derivatives: a new class of potent and selective 5-HT2 antagonists.
Year : 1991
Volume : 34
Issue : 8
First Page : 2477
Last Page : 2483
Authors : Malleron JL, Comte MT, Gueremy C, Peyronel JF, Truchon A, Blanchard JC, Doble A, Piot O, Zundel JL, Huon C.
Abstract : A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.
|
In vitro binding affinity towards dopamine receptor D2 in rat striatal membranes by [3H]sulpiride displacement.
|
None
|
47.0
nM
|
|
Journal : J. Med. Chem.
Title : Examination of the D2/5-HT2 affinity ratios of resolved 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles: an enantioselective approach toward the design of potential atypical antipsychotics.
Year : 1993
Volume : 36
Issue : 21
First Page : 3073
Last Page : 3076
Authors : Mewshaw RE, Abreu ME, Silverman LS, Mathew RM, Tiffany CW, Bailey MA, Karbon EW, Ferkany JW, Kaiser C.
Abstract : Enantiomers of several N-substituted 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles were obtained by the resolution of 2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole and 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole followed by N-alkylation. These, as well as the racemates, were evaluated for their affinity for the 5-HT2 and D2 receptors. Those compounds possessing the 7S,10R stereochemistry were consistently recognized by the 5-HT2 and D2 receptors as the eutomer. 2-Fluoro-11-[4-(4-fluorophenyl)-4-oxobutyl]-5,6,7,8,9,10-hexahydro-7S,10 R- iminocyclohept[b]indole [(7S,10R)-8] had the highest affinity for the 5-HT2 receptor (Ki = 0.80 nM), while its distomer (7R,10S)-8 was the most selective member of this class of bridged gamma-carbolines (D2/5-HT2 = 562). Incorporation of a benzoyl or isosteric benzisoxazole moiety tethered by a four-carbon spacer to a bridged gamma-carboline nucleus, possessing the 7S,10R absolute configuration, produced high affinity ligands for the 5-HT2 and D2 receptors.
|
The compound was tested for its binding affinity towards Dopamine receptor D2 by displacing [3H]5-HT radioligand in rat cerebral cortex
|
None
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyrrole mannich bases as potential antipsychotic agents.
Year : 1992
Volume : 35
Issue : 3
First Page : 552
Last Page : 558
Authors : Scott MK, Martin GE, DiStefano DL, Fedde CL, Kukla MJ, Barrett DL, Baldy WJ, Elgin RJ, Kesslick JM, Mathiasen JR.
Abstract : Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.
|
Binding constant against histamine H1 receptor (in vitro)
|
Cavia porcellus
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Naphthosultam derivatives: a new class of potent and selective 5-HT2 antagonists.
Year : 1991
Volume : 34
Issue : 8
First Page : 2477
Last Page : 2483
Authors : Malleron JL, Comte MT, Gueremy C, Peyronel JF, Truchon A, Blanchard JC, Doble A, Piot O, Zundel JL, Huon C.
Abstract : A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.
|
Inhibition of ACTH response to MK-212 by the compound (0.1 mg/Kg) in rats
|
Rattus norvegicus
|
204.3
ng ml-1
|
|
Journal : J. Med. Chem.
Title : (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo[1,7- bc][2,6]-naphthyridine: a 5-HT2C/2B receptor antagonist with low 5-HT2A receptor affinity.
Year : 1995
Volume : 38
Issue : 1
First Page : 28
Last Page : 33
Authors : Nozulak J, Kalkman HO, Floersheim P, Hoyer D, Schoeffter P, Buerki HR.
Abstract : The indolonaphthyridine 8 is described as a selective 5-HT2C/2B vs 5-HT2A receptor antagonist. The compound was synthesized in seven steps starting from indoline and isonicotinic acid chloride. The key step is a photocyclization of the indolinyl tetrahydropyridinocarbamic acid ethyl ester 4 to the cis-octahydroindolo[1, 7-bc][2,6]naphthyridinecarbamic acid ethyl ester 5. The synthesis was accomplished by reduction with aluminum hydride and racemic resolution. The indolonaphthyridine 8 exerted the binding profile of a selective 5-HT2C receptor ligand (pKD 7.8) and behaved as an antagonist on the 5-HT-induced accumulation of inositol phosphates in pig choroid plexus cells (pKB 7.13). Compound 8 dose-dependently inhibited the ACTH response to MK-212 in rats and the MK-212-induced hypophagic effect with an ID50 value of 0.3 mg/kg sc. Compound 8 acted as a 5-HT2B receptor antagonist at the rat stomach fundus with a pKB value of 7.34.
|
Inhibition of ACTH response to MK-212 by the compound (1 mg/Kg) in rats
|
Rattus norvegicus
|
95.4
ng ml-1
|
|
Journal : J. Med. Chem.
Title : (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo[1,7- bc][2,6]-naphthyridine: a 5-HT2C/2B receptor antagonist with low 5-HT2A receptor affinity.
Year : 1995
Volume : 38
Issue : 1
First Page : 28
Last Page : 33
Authors : Nozulak J, Kalkman HO, Floersheim P, Hoyer D, Schoeffter P, Buerki HR.
Abstract : The indolonaphthyridine 8 is described as a selective 5-HT2C/2B vs 5-HT2A receptor antagonist. The compound was synthesized in seven steps starting from indoline and isonicotinic acid chloride. The key step is a photocyclization of the indolinyl tetrahydropyridinocarbamic acid ethyl ester 4 to the cis-octahydroindolo[1, 7-bc][2,6]naphthyridinecarbamic acid ethyl ester 5. The synthesis was accomplished by reduction with aluminum hydride and racemic resolution. The indolonaphthyridine 8 exerted the binding profile of a selective 5-HT2C receptor ligand (pKD 7.8) and behaved as an antagonist on the 5-HT-induced accumulation of inositol phosphates in pig choroid plexus cells (pKB 7.13). Compound 8 dose-dependently inhibited the ACTH response to MK-212 in rats and the MK-212-induced hypophagic effect with an ID50 value of 0.3 mg/kg sc. Compound 8 acted as a 5-HT2B receptor antagonist at the rat stomach fundus with a pKB value of 7.34.
|
Inhibition of ACTH response to MK-212 by the compound (1 mg/Kg) in rats with solvent
|
Rattus norvegicus
|
37.2
ng ml-1
|
|
Journal : J. Med. Chem.
Title : (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo[1,7- bc][2,6]-naphthyridine: a 5-HT2C/2B receptor antagonist with low 5-HT2A receptor affinity.
Year : 1995
Volume : 38
Issue : 1
First Page : 28
Last Page : 33
Authors : Nozulak J, Kalkman HO, Floersheim P, Hoyer D, Schoeffter P, Buerki HR.
Abstract : The indolonaphthyridine 8 is described as a selective 5-HT2C/2B vs 5-HT2A receptor antagonist. The compound was synthesized in seven steps starting from indoline and isonicotinic acid chloride. The key step is a photocyclization of the indolinyl tetrahydropyridinocarbamic acid ethyl ester 4 to the cis-octahydroindolo[1, 7-bc][2,6]naphthyridinecarbamic acid ethyl ester 5. The synthesis was accomplished by reduction with aluminum hydride and racemic resolution. The indolonaphthyridine 8 exerted the binding profile of a selective 5-HT2C receptor ligand (pKD 7.8) and behaved as an antagonist on the 5-HT-induced accumulation of inositol phosphates in pig choroid plexus cells (pKB 7.13). Compound 8 dose-dependently inhibited the ACTH response to MK-212 in rats and the MK-212-induced hypophagic effect with an ID50 value of 0.3 mg/kg sc. Compound 8 acted as a 5-HT2B receptor antagonist at the rat stomach fundus with a pKB value of 7.34.
|
Compound was evaluated for its activity at membrane-bound receptor (M+L+P fraction) from rat frontal cortex
|
Rattus norvegicus
|
3.467
nM
|
|
Journal : J. Med. Chem.
Title : In vitro labeling of serotonin-S2 receptors: synthesis and binding characteristics of [3H]-7-aminoketanserin.
Year : 1986
Volume : 29
Issue : 9
First Page : 1663
Last Page : 1668
Authors : Wouters W, Janssen CG, Van Dun J, Thijssen JB, Laduron PM.
Abstract : [3H]-7-Aminoketanserin (7-amino-3-[2-[4-(2-tritio-4-fluorobenzoyl)-1- piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione), an amino derivative of the selective serotonin-S2 antagonist ketanserin, was synthesized and tested for in vitro labeling of serotonin-S2 receptors. The compound showed a very high affinity for both membrane-bound and detergent-solubilized serotonin-S2 receptors with KD values of 0.35 and 2.03 nM, respectively. At nanomolar concentrations, binding to serotonin-S1 sites was totally absent. Serotonin-S2 receptor binding was characterized by a slow dissociation and a very low nonspecific binding. In rat frontal cortex preparations, binding could be displaced by nanomolar concentrations of different serotonin antagonists and micromolar concentrations of serotonin agonists. Compounds with other pharmacological profiles were poorly or not active. Introduction of an amino function in this new radioligand led to a decreased lipophilicity. Therefore, besides being a valuable radioligand for routine binding studies, [3H]-7-aminoketanserin will probably be a good ligand for labeling serotonin-S2 receptors on intact cells.
|
Compound was evaluated for its activity at solubilized receptor (CHAPS/salt-solubilized preparation) from rat frontal cortex
|
Rattus norvegicus
|
14.13
nM
|
|
Journal : J. Med. Chem.
Title : In vitro labeling of serotonin-S2 receptors: synthesis and binding characteristics of [3H]-7-aminoketanserin.
Year : 1986
Volume : 29
Issue : 9
First Page : 1663
Last Page : 1668
Authors : Wouters W, Janssen CG, Van Dun J, Thijssen JB, Laduron PM.
Abstract : [3H]-7-Aminoketanserin (7-amino-3-[2-[4-(2-tritio-4-fluorobenzoyl)-1- piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione), an amino derivative of the selective serotonin-S2 antagonist ketanserin, was synthesized and tested for in vitro labeling of serotonin-S2 receptors. The compound showed a very high affinity for both membrane-bound and detergent-solubilized serotonin-S2 receptors with KD values of 0.35 and 2.03 nM, respectively. At nanomolar concentrations, binding to serotonin-S1 sites was totally absent. Serotonin-S2 receptor binding was characterized by a slow dissociation and a very low nonspecific binding. In rat frontal cortex preparations, binding could be displaced by nanomolar concentrations of different serotonin antagonists and micromolar concentrations of serotonin agonists. Compounds with other pharmacological profiles were poorly or not active. Introduction of an amino function in this new radioligand led to a decreased lipophilicity. Therefore, besides being a valuable radioligand for routine binding studies, [3H]-7-aminoketanserin will probably be a good ligand for labeling serotonin-S2 receptors on intact cells.
|
Compound was evaluated for its activity at membrane-bound receptor (M+L+P fraction) from rat frontal cortex
|
Rattus norvegicus
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : In vitro labeling of serotonin-S2 receptors: synthesis and binding characteristics of [3H]-7-aminoketanserin.
Year : 1986
Volume : 29
Issue : 9
First Page : 1663
Last Page : 1668
Authors : Wouters W, Janssen CG, Van Dun J, Thijssen JB, Laduron PM.
Abstract : [3H]-7-Aminoketanserin (7-amino-3-[2-[4-(2-tritio-4-fluorobenzoyl)-1- piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione), an amino derivative of the selective serotonin-S2 antagonist ketanserin, was synthesized and tested for in vitro labeling of serotonin-S2 receptors. The compound showed a very high affinity for both membrane-bound and detergent-solubilized serotonin-S2 receptors with KD values of 0.35 and 2.03 nM, respectively. At nanomolar concentrations, binding to serotonin-S1 sites was totally absent. Serotonin-S2 receptor binding was characterized by a slow dissociation and a very low nonspecific binding. In rat frontal cortex preparations, binding could be displaced by nanomolar concentrations of different serotonin antagonists and micromolar concentrations of serotonin agonists. Compounds with other pharmacological profiles were poorly or not active. Introduction of an amino function in this new radioligand led to a decreased lipophilicity. Therefore, besides being a valuable radioligand for routine binding studies, [3H]-7-aminoketanserin will probably be a good ligand for labeling serotonin-S2 receptors on intact cells.
|
Compound was evaluated for its activity at solubilized receptor (CHAPS/salt-solubilized preparation) from rat frontal cortex
|
Rattus norvegicus
|
7.06
nM
|
|
Journal : J. Med. Chem.
Title : In vitro labeling of serotonin-S2 receptors: synthesis and binding characteristics of [3H]-7-aminoketanserin.
Year : 1986
Volume : 29
Issue : 9
First Page : 1663
Last Page : 1668
Authors : Wouters W, Janssen CG, Van Dun J, Thijssen JB, Laduron PM.
Abstract : [3H]-7-Aminoketanserin (7-amino-3-[2-[4-(2-tritio-4-fluorobenzoyl)-1- piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione), an amino derivative of the selective serotonin-S2 antagonist ketanserin, was synthesized and tested for in vitro labeling of serotonin-S2 receptors. The compound showed a very high affinity for both membrane-bound and detergent-solubilized serotonin-S2 receptors with KD values of 0.35 and 2.03 nM, respectively. At nanomolar concentrations, binding to serotonin-S1 sites was totally absent. Serotonin-S2 receptor binding was characterized by a slow dissociation and a very low nonspecific binding. In rat frontal cortex preparations, binding could be displaced by nanomolar concentrations of different serotonin antagonists and micromolar concentrations of serotonin agonists. Compounds with other pharmacological profiles were poorly or not active. Introduction of an amino function in this new radioligand led to a decreased lipophilicity. Therefore, besides being a valuable radioligand for routine binding studies, [3H]-7-aminoketanserin will probably be a good ligand for labeling serotonin-S2 receptors on intact cells.
|
In vitro binding affinity towards serotonin 5-HT2A receptor in rat cortical membranes using [3H]ketanserin as radioligand
|
None
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1,1-diphenyl-3-dialkylamino-1-silacyclopentane derivatives: A new class of potent and selective 5-HT2A antagonists
Year : 1994
Volume : 4
Issue : 3
First Page : 415
Last Page : 420
Authors : Damour D, Barreau M, Dutruc-Rosset G, Doble A, Piot O, Mignani S
|
The inhibition of compound was measured for 5 min in head twitches of mice induced by 5-HTP(100 mg/kg, ip) at the dose of 10 mg/kg
|
Mus musculus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.
Year : 1992
Volume : 35
Issue : 1
First Page : 189
Last Page : 194
Authors : Watanabe Y, Usui H, Kobayashi S, Yoshiwara H, Shibano T, Tanaka T, Morishima Y, Yasuoka M, Kanao M.
Abstract : A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.
|
The inhibition of compound was measured for 5 min in head twitches of mice induced by 5-HTP(100 mg/kg, ip) at the dose of 1 mg/kg
|
Mus musculus
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.
Year : 1992
Volume : 35
Issue : 1
First Page : 189
Last Page : 194
Authors : Watanabe Y, Usui H, Kobayashi S, Yoshiwara H, Shibano T, Tanaka T, Morishima Y, Yasuoka M, Kanao M.
Abstract : A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.
|
The inhibition of compound was measured for 5 min in head twitches of mice induced by 5-HTP(100 mg/kg, ip) at the dose of 3 mg/kg
|
Mus musculus
|
95.0
%
|
|
Journal : J. Med. Chem.
Title : Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.
Year : 1992
Volume : 35
Issue : 1
First Page : 189
Last Page : 194
Authors : Watanabe Y, Usui H, Kobayashi S, Yoshiwara H, Shibano T, Tanaka T, Morishima Y, Yasuoka M, Kanao M.
Abstract : A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.
|
Displacement of [3H]ketanserin from 5HT2A receptor in Sprague-Dawley rat brain by liquid scintillation spectroscopy
|
Rattus norvegicus
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The role of lipophilicity in determining binding affinity and functional activity for 5-HT2A receptor ligands.
Year : 2008
Volume : 16
Issue : 8
First Page : 4661
Last Page : 4669
Authors : Parker MA, Kurrasch DM, Nichols DE.
Abstract : The lipophilicity of a set of 5-HT(2A) ligands was determined using immobilized-artificial-membrane chromatography, a method that generates values well correlated with octanol-water partition coefficients. For agonists, a highly significant linear correlation was observed between binding affinity and lipophilicity. For ligands exhibiting partial agonist or antagonist properties, the lipophilicity was consistently higher than would be expected for an agonist of comparable affinity. The results suggest a possible method for distinguishing agonists from antagonists in high-throughput screening when a direct assay for functional activity is either unavailable or impractical.
|
Displacement of [3H]MDL100907 from 5HT2A receptor in Sprague-Dawley rat brain by liquid scintillation spectroscopy
|
Rattus norvegicus
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The role of lipophilicity in determining binding affinity and functional activity for 5-HT2A receptor ligands.
Year : 2008
Volume : 16
Issue : 8
First Page : 4661
Last Page : 4669
Authors : Parker MA, Kurrasch DM, Nichols DE.
Abstract : The lipophilicity of a set of 5-HT(2A) ligands was determined using immobilized-artificial-membrane chromatography, a method that generates values well correlated with octanol-water partition coefficients. For agonists, a highly significant linear correlation was observed between binding affinity and lipophilicity. For ligands exhibiting partial agonist or antagonist properties, the lipophilicity was consistently higher than would be expected for an agonist of comparable affinity. The results suggest a possible method for distinguishing agonists from antagonists in high-throughput screening when a direct assay for functional activity is either unavailable or impractical.
|
Cardiotoxicity in iv dosed Dunkin-Hartley guinea pig assessed as drug level required to evoke 50 ms QTc prolongation administered as 3 fold cumulative doses measured every 10 seconds at end of every 20 mins follow up period of individual dose by ECG
|
Cavia porcellus
|
0.19
umol/Kg
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of "toxicophoric" features for predicting drug-induced QT interval prolongation.
Year : 2008
Volume : 43
Issue : 11
First Page : 2479
Last Page : 2488
Authors : Coi A, Massarelli I, Testai L, Calderone V, Bianucci AM.
Abstract : Drugs delaying cardiac repolarization by blockade of hERG K(+) channel generally prolong the QT interval of the electrocardiogram, an effect regarded as a cardiac risk factor with the potential to cause 'torsade des pointes'-type arrhythmias in humans. The present study applied a homology building technique and molecular dynamics simulations to model the pore of hERG K(+) channel. A docking analysis was then performed on selected ligands which were classified as QT-prolonging or non-prolonging after experimental measurements in in vivo anesthetized guinea pig. The results of this structural analysis provided a "toxicophoric" model that was further exploited to inspect a dataset of known QT-prolonging/non-prolonging molecules. The emerging major chemical features to be avoided, in order to obtain cardiac safe therapeutic agents, comprise the simultaneous presence of (i) a protonated nitrogen atom within an observed range of distances from a heteroatom; (ii) aromatic groups capable of interacting within an area defined by Gly657 residues of the pore or within an area located at the top of the longitudinal axis of the pore. Moreover, additional hydrophobic moieties interacting with one of the equatorial cavities located in the area near-by Tyr652 residues and/or with a hydrophobic ring defined by Phe656 residues should be avoided.
|
Binding affinity to 5HT1A receptor
|
None
|
251.19
nM
|
|
Journal : J. Med. Chem.
Title : Physical binding pocket induction for affinity prediction.
Year : 2009
Volume : 52
Issue : 19
First Page : 6107
Last Page : 6125
Authors : Langham JJ, Cleves AE, Spitzer R, Kirshner D, Jain AN.
Abstract : Computational methods for predicting ligand affinity where no protein structure is known generally take the form of regression analysis based on molecular features that have only a tangential relationship to a protein/ligand binding event. Such methods have limited utility when structural variation moves beyond congeneric series. We present a novel approach based on the multiple-instance learning method of Compass, where a physical model of a binding site is induced from ligands and their corresponding activity data. The model consists of molecular fragments that can account for multiple positions of literal protein residues. We demonstrate the method on 5HT1a ligands by training on a series with limited scaffold variation and testing on numerous ligands with variant scaffolds. Predictive error was between 0.5 and 1.0 log units (0.7-1.4 kcal/mol), with statistically significant rank correlations. Accurate activity predictions of novel ligands were demonstrated using a validation approach where a small number of ligands of limited structural variation known at a fixed time point were used to make predictions on a blind test set of widely varying molecules, some discovered at a much later time point.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
96.72
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
101.71
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Displacement of [3H]mesulergine from human recombinant 5-HT2C receptor expressed in Flp-IN HEK cell membrane after 90 mins by scintillation counting method
|
Homo sapiens
|
1.8
nM
|
|
Journal : MedChemComm
Title : Identification of tris-(phenylalkyl)amines as new selective h5-HT2Breceptor antagonists
Year : 2015
Volume : 6
Issue : 4
First Page : 601
Last Page : 605
Authors : Ponnala S, Kapadia N, Harding WW
|
Inhibition of 5-HTP-induced head twitch response in ddY mouse at >=1 mg/kg, po administered 1 hr before 5-HTP injection measured after 30 mins relative to untreated control
|
Mus musculus
|
80.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : 5-HT2 receptor affinity, docking studies and pharmacological evaluation of a series of 1,3-disubstituted thiourea derivatives.
Year : 2016
Volume : 116
First Page : 173
Last Page : 186
Authors : Bielenica A, Kędzierska E, Koliński M, Kmiecik S, Koliński A, Fiorino F, Severino B, Magli E, Corvino A, Rossi I, Massarelli P, Kozioł AE, Sawczenko A, Struga M.
Abstract : A series of 10 thiourea derivatives have been synthesized by the reaction of aromatic amine with a substituted aryl (compounds 1-3, 6-8) and alkylphenyl (4, 5, 9, 10) isothiocyanates. Their in vitro and in vivo pharmacological properties were studied. Among the evaluated compounds, two displayed very high affinity for the 5-HT2A receptor (1-0.043 nM and 5-0.6 nM), being selective over the 5-HT2C receptor. Derivatives 3, 5, 9, 10 by 70-89% diminished L-5-HTP-induced head twitch episodes. Compounds 1 and 5 as the 5-HT2A receptor antagonists produced a dose-dependent decrease in the number of DOI-elicited HTR. Compounds 1-5 strongly reduced amphetamine-evoked hyperactivity in rodents. In another test, 1 and 2 caused hyperthermia in mice, whereas 9 and 10 led to hypothermia. Antinociceptive and anticonvulsant properties of selected derivatives were demonstrated. Molecular docking studies using a homology model of 5-HT2A revealed a significant role of hydrogen bonds between both thiourea NH groups and Asp155/Tyr370 residues, as well as π-π interaction with Phe339.
|
Displacement of [3H]mesulergine from human 5-HT2C receptor measured after 90 mins by microbeta scintillation counting method
|
Homo sapiens
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New halogenated tris-(phenylalkyl)amines as h5-HT2B receptor ligands.
Year : 2016
Volume : 26
Issue : 14
First Page : 3216
Last Page : 3219
Authors : Kapadia N, Ahmed S, Harding WW.
Abstract : A series of compounds in which various halogen substituents were incorporated into a phenyl ring of a tris-(phenylalkyl)amine scaffold, was synthesized and evaluated for affinity to h5-HT2 receptors. In general, all compounds were found to have good affinity for the 5-HT2B receptor and were selective over 5-HT2A and 5-HT2C receptors. Compound 9i was the most selective compound in this study and is the highest affinity 5-HT2B receptor ligand bearing a tris-(phenylalkyl)amine scaffold to date.
|
Displacement of [3H]LSD from human 5HT2C receptor expressed in HEKT cell membranes after 1.5 hrs by liquid scintillation counting method
|
Homo sapiens
|
1.9
nM
|
|
Journal : MedChemComm
Title : Pharmacophore-based tailoring of biphenyl amide derivatives as selective 5-hydroxytryptamine 2B receptor antagonists.
Year : 2018
Volume : 9
Issue : 6
First Page : 1069
Last Page : 1075
Authors : Gabr MT, Abdel-Raziq MS.
Abstract : We designed and synthesized a new biphenyl amide-tryptamine hybrid molecule <b>7</b> utilizing a pharmacophore-based approach as a 5-HT<sub>2B</sub> antagonist. The hybrid compound <b>7</b> was evaluated for its affinity to a panel of seven 5-HT receptors, demonstrating high selectivity for the 5-HT<sub>2B</sub> receptor. Functional assays revealed potent antagonism of 5-HT<sub>2B</sub> by <b>7</b> with an IC<sub>50</sub> value of 14.1 nM. Moreover, compound <b>7</b> possessed a desirable <i>in vitro</i> pharmacokinetic profile and maintained its antagonistic potency in the presence of physiological concentrations of serum proteins. The design approach implemented in this investigation would facilitate the development of a second generation of highly selective and potent 5-HT<sub>2B</sub> antagonists.
|
Binding affinity to 5HT2A receptor (unknown origin)
|
Homo sapiens
|
0.45
nM
|
|
Journal : Eur J Med Chem
Title : Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening.
Year : 2019
Volume : 164
First Page : 378
Last Page : 390
Authors : Velnati S, Ruffo E, Massarotti A, Talmon M, Varma KSS, Gesu A, Fresu LG, Snow AL, Bertoni A, Capello D, Tron GC, Graziani A, Baldanzi G.
Abstract : As part of an effort to identify druggable diacylglycerol kinase alpha (DGKα) inhibitors, we used an in-silico approach based on chemical homology with the two commercially available DGKα inhibitors R59022 and R59949. Ritanserin and compound AMB639752 emerged from the screening of 127 compounds, showing an inhibitory activity superior to the two commercial inhibitors, being furthermore specific for the alpha isoform of diacylglycerol kinase. Interestingly, AMB639752 was also devoid of serotoninergic activity. The ability of both ritanserin and AMB639752, by inhibiting DGKα in intact cells, to restore restimulation induced cell death (RICD) in SAP deficient lymphocytes was also tested. Both compounds restored RICD at concentrations lower than the two previously available inhibitors, indicating their potential use for the treatment of X-linked lymphoproliferative disease 1 (XLP-1), a rare genetic disorder in which DGKα activity is deregulated.
|
Binding affinity to 5HT2C receptor (unknown origin)
|
Homo sapiens
|
0.71
nM
|
|
Journal : Eur J Med Chem
Title : Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening.
Year : 2019
Volume : 164
First Page : 378
Last Page : 390
Authors : Velnati S, Ruffo E, Massarotti A, Talmon M, Varma KSS, Gesu A, Fresu LG, Snow AL, Bertoni A, Capello D, Tron GC, Graziani A, Baldanzi G.
Abstract : As part of an effort to identify druggable diacylglycerol kinase alpha (DGKα) inhibitors, we used an in-silico approach based on chemical homology with the two commercially available DGKα inhibitors R59022 and R59949. Ritanserin and compound AMB639752 emerged from the screening of 127 compounds, showing an inhibitory activity superior to the two commercial inhibitors, being furthermore specific for the alpha isoform of diacylglycerol kinase. Interestingly, AMB639752 was also devoid of serotoninergic activity. The ability of both ritanserin and AMB639752, by inhibiting DGKα in intact cells, to restore restimulation induced cell death (RICD) in SAP deficient lymphocytes was also tested. Both compounds restored RICD at concentrations lower than the two previously available inhibitors, indicating their potential use for the treatment of X-linked lymphoproliferative disease 1 (XLP-1), a rare genetic disorder in which DGKα activity is deregulated.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
25.0
%
|
|
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
|
1.27
%
|
|
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
|
1.27
%
|
|
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.
