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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
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
Substances
-
Antipsychotic Agents
-
Benzazepines
-
Dopamine D2 Receptor Antagonists
-
Pyrroles
-
Receptor, Serotonin, 5-HT2A
-
Receptors, Dopamine D2
-
Serotonin 5-HT2 Receptor Antagonists
-
Palladium