Article: Novel atypical antipsychotic agents: rational design, an efficient palladium-catalyzed route, and pharmacological studies.
Journal of medicinal chemistry
2005 Volume 48, Issue 6, Page(s) 1705–1708
Abstract: Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK(i) 5-HT(2A)/D(2) ratio. 5a, obtained by a new palladium-catalyzed three-step synthesis, was ...
Abstract | Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK(i) 5-HT(2A)/D(2) ratio. 5a, obtained by a new palladium-catalyzed three-step synthesis, was selected for further pharmacological and biochemical investigations and showed atypical antipsychotic properties in vivo. 5a was active on conditioned avoidance response at 0.56 mg/kg, it had low cataleptic potential and proved to be better than ST1899, clozapine, and olanzapine, representing a new clinical candidate. |
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MeSH term(s) | Animals ; Antipsychotic Agents/chemical synthesis ; Antipsychotic Agents/chemistry ; Antipsychotic Agents/pharmacology ; Avoidance Learning/drug effects ; Benzazepines/chemical synthesis ; Benzazepines/chemistry ; Benzazepines/pharmacology ; Binding Sites ; Catalepsy/chemically induced ; Catalysis ; Cell Line ; Crystallography, X-Ray ; Dopamine D2 Receptor Antagonists ; Drug Design ; In Vitro Techniques ; Mice ; Models, Molecular ; Molecular Conformation ; Palladium ; Pyrroles/chemical synthesis ; Pyrroles/chemistry ; Pyrroles/pharmacology ; Radioligand Assay ; Rats ; Receptor, Serotonin, 5-HT2A/chemistry ; Receptors, Dopamine D2/chemistry ; Serotonin 5-HT2 Receptor Antagonists ; Structure-Activity Relationship |
Chemical Substances | Antipsychotic Agents ; Benzazepines ; Dopamine D2 Receptor Antagonists ; Pyrroles ; Receptor, Serotonin, 5-HT2A ; Receptors, Dopamine D2 ; Serotonin 5-HT2 Receptor Antagonists ; Palladium (5TWQ1V240M) |
Language | English |
Publishing date | 2005-03-24 |
Publishing country | United States |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 218133-2 |
ISSN | 1520-4804 ; 0022-2623 |
ISSN (online) | 1520-4804 |
ISSN | 0022-2623 |
DOI | 10.1021/jm049629t |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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