DISCOVERY OF POTENTIAL ANTIDEPRESSANT AGENTS - NOVEL 3-ARYLPYRROLIDINES WITH DUAL MECHANISM OF ACTION ON NEUROTRANSMISSION

A series of 3-arylpyrrolidines 4 and related compounds were synthesize d and examined for antidepressant-like activity. Our hypothesis was th at the dual action of these agents, namely inhibition of the uptake of biogenic amines and blockade of presynaptic alpha2 receptors, should increase CNS levels of the respective biogenic amines in the synaptic cleft. This would enhance the potential utility of these agents as ant idepressants. These compounds are inhibitors of the reuptake of norepi nephrine in the nerve terminus of rat hypothalamus and are also potent antagonists of alpha2 receptors measured both in vitro and in vivo. T he rational design and the methodology developed for synthesis of thes e compounds is presented.