- Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor
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Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.
- Fyfe, Tim J.,Kellam, Barrie,Sykes, David A.,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert,Charlton, Steven J.,Mistry, Shailesh N.
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p. 9488 - 9520
(2019/11/11)
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- DIPHENYLBUTYPIPERIDINE AUTOPHAGY INDUCERS
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Autophagy inducing compounds, methods of their preparation and use, and kits containg said compounds are disclosed herein.
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Page/Page column 7; 84-85
(2011/12/02)
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- Synthesis and SAR study of diphenylbutylpiperidines as cell autophagy inducers
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A novel series of diphenylbutylpiperidines as autophagy inducers was described and extensive SAR studies resulted in derivatives (15d-e, 15i-j) with 10-fold greater activity than the lead compounds 1 and 2. Meanwhile, a new synthetic route to diphenylbutyl bromide (6) from bromobenzene and γ-butyrolactone was also reported here.
- Chen, Gang,Xia, Hongguang,Cai, Yu,Ma, Dawei,Yuan, Junying,Yuan, Chengye
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supporting information; experimental part
p. 234 - 239
(2011/02/26)
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- INDAZOLE COMPOUND AND PHARMACEUTICAL USE THEREOF
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The present invention can provide a cancer treatment drug containing, as an active ingredient, a substance selected from the group consisting of an indazole compound of the following formula (I), a pharmaceutically acceptable salt, a hydrate, a water adduct and a solvate:
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Page/Page column 31
(2010/11/24)
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- Studies on the N-dealkylated metabolite of haloperidol
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The recent detection of 4-Chlorophenyl-4-piperidinol (CPPO), in rats fed haloperidol and the subsequent demonstration that CPPO produces a freezing action in frogs, has encouraged us to study the structural features that might be responsible for the freezing action. In this study, we have shown that removal of the chloro from the phenyl ring has little effect on the freezing action and the removal of the tertiary alcohol from the piperidine only decreases somewhat the effectiveness of the freezing action. In addition, since replacing the piperidine ring with tetrahydropyridine and piperazine moieties led to compounds without the freezing action, and because 4-phenylpiperidine is the common entity in all the compounds with the freezing action, it is reasonable to suggest that the 4-phenylpiperidine moiety may be responsible for the freezing action observed in CPPO.
- Lyles-Eggleston,Margaret,McCollough,Craig,Fan,Pingchen,Ablordeppey,Mardenborough, Joy H.,Leroy,Ablordeppey,Seth,Borne
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p. 686 - 695
(2007/10/03)
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- Derivatives of (AZA)naphthalenesultam, their preparation and compositions containing them
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This invention relates to a compound STR1 in which R 1 representsa 1,2,3,6-tetrahydro-1-pyridyl radical substituted in the 4-position by (a) a phenyl radical, (b) a phenyl radical substituted by a halogen atom or an alkyl, hydroxy or alkoxy radical, (c) a 3-indolyl radical, (d) a 3-indolyl radical substituted on the nitrogen atom by an alkyl or alkylcarbonyl radical and/or in the 5-position by a halogen atom or (e) a 3-(5-hydroxyindolyl) radical.a 1-piperazinyl radical substituted in the 4-position by (a) a phenyl radical, (b) a phenyl radical substituted by an alkoxy, alkyl, hydroxy, nitro or amino radical or a halogen atom, (c) a 1,2-benzisothiazol-3-yl radical, (d) a 1,2-benzisoxazol-3-yl radical or (e) a 2-pyridyl radical.a piperidino radical substituted in the 4-position by (a) a phenyl radical, (b) a phenyl radical substituted by a halogen atom or a hydroxy, alkyl or alkoxy radical, (c) two phenyl radicals, (d) a bis(4-fluorophenyl)methylene radical, (e) a 4-fluorobenzoyl radical, (f) a 2-oxo-1-benzimidazolinyl radical, (g) a 2-oxo-1-benzimidazolinyl radical substituted in the 3-position by an alkylcarbonyl or benzoyl radical, (b) a hydroxy radical and a phenyl radical optionally substituted with an alkyl, alkoxy or hydroxy radical or a halogen atom, (i) a 3-indolyl radical, (j) a 3-indolyl radical substituted on the nitrogen atom by an alkyl or alkylcarbonyl radical and/or in the 5-position by a halogen atom or (k) a 3-(5-hydroxyindolyl) radical.either:R 2 and R 3, which are identical, represent a hydrogen or halogen atom and R 4 represents a hydrogen atom orR 2 and R 4 represent a hydrogen atom and R 3 represents a halogen atom or an acetylamino radical orR 2 and R 3 represent a hydrogen atom and R 4 represents a halogen atom and R 5 represents a --CH group.or R 2, R 3 and R 4 represent a hydrogen atom and R 5 represents a nitrogen atom.R 6 represents an alkylene chain containing 2 to 4 carbon atoms or a propylene chain substituted in the 1- or 3-position by an alkyl radical or in the 2-position by an alkyl, alkoxy, hydroxy, dialkylamino, piperidino, morpholino or thiomorpholino radical,with the reservation that when R 6 represents a propylene radical substituted in the 2-position by a dialkylamino, piperidino, morpholino or thiomorpholino radical, R 1 cannot be a radical containing a hydroxy radical, and their salts, are useful in therapy for their ability to block serotonin receptors.
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- New phenylazacycloalkanes
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New 4-(phenyl)-piperidine compounds of the general formula I STR1 in which R1 represents hydrogen or lower alkyl, Ph represents a p-phenylene group optionally substituted by lower alkyl, lower alkoxy, nitro and/or halogen, and R2 represents lower alkyl, and pharmaceutically acceptable acid addition salts thereof are useful as antidepressant agents.
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