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N-aryl-N'-benzylpiperazines as potential antipsychotic agents
A B Reitz1, E W Baxter, D J Bennett
1R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA.
Journal of Medicinal Chemistry
|October 13, 1995
Summary
New N1-(2-alkoxyphenyl)piperazines with N4-benzyl groups were synthesized and tested for antipsychotic potential. Compounds with amide, imide, and hydantoin groups showed promising D2, 5-HT1A, and alpha 1-adrenergic receptor activity.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Pharmacology
Background:
- Piperazine derivatives are explored for potential therapeutic applications.
- Antipsychotic drug discovery often targets dopamine D2 and serotonin 5-HT1A receptors.
Purpose of the Study:
- To synthesize and evaluate novel N1-(2-alkoxyphenyl)piperazine derivatives.
- To assess their potential as antipsychotic agents through in vitro and in vivo studies.
Main Methods:
- Synthesis of N1-(2-alkoxyphenyl)piperazines with diverse N4-benzyl functionalities (alcohol, amide, imide, hydantoin).
- Evaluation using the conditioned avoidance response (CAR) test for in vivo antipsychotic activity.
- In vitro receptor-binding assays for D2, 5-HT1A, and alpha 1-adrenergic receptors.
Main Results:
- Compounds with amide, lactam, and imide groups exhibited good biological activity.
- N1-substituted hydantoin derivative (24) showed good activity, while N3/C5 substitutions were inactive.
- Benzyl and benzhydryl alcohol derivatives (40-48) demonstrated excellent in vivo CAR activity and modest receptor binding.
- Uracil congener (34) displayed modest D2 affinity and excellent in vivo activity.
Conclusions:
- Structural modifications, particularly amide, imide, and N1-hydantoin functionalities, are crucial for antipsychotic activity.
- Benzyl and benzhydryl alcohol derivatives represent promising leads for further antipsychotic drug development.
- The study highlights the importance of specific structural features for receptor affinity and in vivo efficacy.