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Pyrrole mannich bases as potential antipsychotic agents
M K Scott1, G E Martin, D L DiStefano
1Department of Biological Research, McNeil Pharmaceutical, R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477.
Journal of Medicinal Chemistry
|February 17, 1992
Summary
New pyrrole Mannich bases derived from arylpiperazines show potent antipsychotic potential. These compounds effectively inhibit conditioned avoidance responding (CAR) and exhibit strong dopamine D-2 and serotonin 5-HT-1A receptor binding, with reduced risk of side effects.
Area of Science:
- Medicinal Chemistry
- Neuropharmacology
- Drug Discovery
Background:
- Arylpiperazines previously showed affinity for serotonin 5-HT-1A and 5-HT-1B receptors and weak interaction with dopamine receptors.
- These compounds demonstrated potential antipsychotic activity by inhibiting conditioned avoidance responding (CAR) in rats.
Purpose of the Study:
- To synthesize and evaluate novel pyrrole Mannich bases derived from arylpiperazines.
- To assess the affinity of these new compounds for dopamine D-2 and serotonin 5-HT-1A receptors.
- To determine the potential antipsychotic efficacy and safety profile of these novel agents.
Main Methods:
- Synthesis of pyrrole Mannich bases (compounds 10-44) from arylpiperazines.
- In vitro binding assays for dopamine D-2 and serotonin 5-HT-1A receptors.
- In vivo evaluation of conditioned avoidance responding (CAR) inhibition and catalepsy in rats.
Main Results:
- The novel pyrrole Mannich bases exhibited potent inhibition of CAR when administered orally.
- These compounds demonstrated strong binding affinity for both dopamine D-2 and serotonin 5-HT-1A receptors.
- Some compounds effectively inhibited CAR and D-2 binding without inducing catalepsy, suggesting reduced extrapyramidal side effect liability.
Conclusions:
- Pyrrole Mannich bases represent a promising class of potential antipsychotic agents.
- The observed D-2 receptor affinity and CAR inhibition support their antipsychotic potential.
- The lack of catalepsy in some compounds indicates a potentially improved safety profile regarding extrapyramidal side effects and tardive dyskinesias.