Molecular field analysis of clozapine analogs in the development of a pharmacophore model of antipsychotic drug action

In an attempt to elucidate some aspects of clozapine’s favorable receptor binding profile, we modeled a series of 30 clozapine analogs using a pharmacophore based on the ligands octoclothepin and tefludazine. Molecular field analysis using CoMFA combined with HINT® was carried out on published D 2 r...

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Bibliographic Details
Published in:Journal of molecular graphics & modelling 2001-01, Vol.19 (5), p.417-426
Main Authors: Tehan, Benjamin G., Lloyd, Edward J., Wong, Margaret G.
Format: Article
Language:English
Subjects:
antipsychotic
Antipsychotic Agents - chemistry
clozapine
Clozapine - chemistry
CoMFA
Computer Simulation
Dibenzothiepins - chemistry
dopamine
Dopamine D2 Receptor Antagonists
HINT
Ligands
Models, Molecular
Molecular Conformation
Molecular Structure
pharmacophore
Piperazines - chemistry
QSAR
schizophrenia
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Summary:In an attempt to elucidate some aspects of clozapine’s favorable receptor binding profile, we modeled a series of 30 clozapine analogs using a pharmacophore based on the ligands octoclothepin and tefludazine. Molecular field analysis using CoMFA combined with HINT® was carried out on published D 2 receptor binding affinities. Several alternative alignments of the analogs gave r 2 values in the range of 0.8–0.95. The final model had good predictive abilities with q 2 > 0.6 and r 2 > 0.9. This provides an excellent framework to aid in the design of novel antipsychotics with diminished propensity to produce clinically limiting side effects. © 2001 by Elsevier Science Inc.
ISSN:1093-3263
1873-4243
DOI:10.1016/S1093-3263(00)00101-7