PIPERAZINYLALKYL HETEROCYCLES AS POTENTIAL ANTIPSYCHOTIC AGENTS

We recently reported on a series of pyrrole Mannich bases orally activ e in inhibiting the conditioned avoidance response (CAR) in rats. Thes e compounds exhibit affinity for both Dg and 6-HT1A receptors, and som e are noncataleptogenic. Such a profile suggests that they may be pote ntial antipsychotic agents which lack the propensity for causing extra pyramidal side effects and tardive dyskinesias in humans. One of these compounds, inyl]methyl]-1H-pyrrol-2-yl]methyl]-2-piperidinone (RWJ 25 730, 1), was chosen for further development but found to be unstable i n dilute acid. In order to improve stability, we replaced the pyrrole methylene linkage to the piperazine ring with ethylene, employed ethyl ene and dicarbonyl as linkers between the lactam and the pyrrole ring, placed electron-withdrawing groups on the pyrrole ring, and substitut ed acyclic amide for lactam. In addition, we replaced the pyrrole segm ent with other heterocycles including thiophene, furan, isoxazole, iso xazoline, and pyridine. Generally, replacement of the N-methylpyrrole segment with thiophene, furan, isoxazoline, or pyridine afforded compo unds equipotent with 1 in CAR, which were more stable in dilute acid. In the case of side chain or lactam modifications, CAR activity was si gnificantly decreased or abolished, with the exception of 6. For the m ost part, the modifications to 1 resulted in the decrease or loss of D -2 receptor binding. However, within this series, 5-HT1A receptor bind ing was greatly increased, with thiophene 40 exhibiting an IC50 of 0.0 7 nM. The CAR activities of pyrroles 6 and 12, thiophene 40, furans 44 -47, isoxazolines 49 and 50, and pyridine 54 coupled with their weak o r nonexistent D-2 binding and strong 5-HT1A binding suggest that they may be acting via a nondopaminergic mechanism or that dopaminergic act ive metabolites are responsible. Pyrrole 6 and furans 44 and 47 show p romise as antipsychotic agents based on their CAR activity, receptor-b inding profile, and solution stability.