Discovery of potential antidepressant agents: Novel 3-arylpyrrolidines with dual mechanism of action on neurotransmission

Abstract

A series of 3-arylpyrrolidines 4 and related compounds were synthesized and examined for antidepressant-like activity. Our hypothesis was that the dual action of these agents, namely inhibition of the uptake of biogenic amines and blockade of presynaptic α2 receptors, should increase CNS levels of the respective biogenic amines in the synaptic cleft. This would enhance the potential utility of these agents as antidepressants. These compounds are inhibitors of the reuptake of norepinephrine in the nerve terminus of rat hypothalamus and are also potent antagonists of α2 receptors measured both in vitro and in vivo. The rational design and the methodology developed for synthesis of these compounds is presented. © 1994 IUPAC