Novel Atypical Antipsychotic Agents:  Rational Design, an Efficient Palladium-Catalyzed Route, and Pharmacological Studies

Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK i 5-HT2A/D2 ratio. 5a, obtained by a new palladium-catalyzed three-step synthesis, was selected for further pharmacological and biochemic...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-03, Vol.48 (6), p.1705-1708
Main Authors: Campiani, Giuseppe, Butini, Stefania, Fattorusso, Caterina, Trotta, Francesco, Gemma, Sandra, Catalanotti, Bruno, Nacci, Vito, Fiorini, Isabella, Cagnotto, Alfredo, Mereghetti, Ilario, Mennini, Tiziana, Minetti, Patrizia, Di Cesare, M. Assunta, Stasi, M. Antonietta, Di Serio, Stefano, Ghirardi, Orlando, Tinti, Ornella, Carminati, Paolo
Format: Article
Language:English
Subjects:
Animals
Antipsychotic Agents - chemical synthesis
Antipsychotic Agents - chemistry
Antipsychotic Agents - pharmacology
Avoidance Learning - drug effects
Benzazepines - chemical synthesis
Benzazepines - chemistry
Benzazepines - pharmacology
Binding Sites
Biological and medical sciences
Catalepsy - chemically induced
Catalysis
Cell Line
Crystallography, X-Ray
Dopamine D2 Receptor Antagonists
Drug Design
In Vitro Techniques
Medical sciences
Mice
Models, Molecular
Molecular Conformation
Neuropharmacology
Palladium
Pharmacology. Drug treatments
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
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
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Description
Summary:Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK i 5-HT2A/D2 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049629t