A series of conformationally constrained pyrrolidine derivatives were synthesized and evaluated for their affinity at a4�2 nicotine acetylcholine receptors and for antidepressant properties in rats. The introduction of rigidity in the pyrrolidine ring exerted a profound influence on both receptor binding and antidepressant effects. Substitution of different groups in the heteroaromatic group which is connected to the pyrrolidine ring through ether linkage has also shown the influence on the antidepressant properties. These results demonstrated that structural requirements for receptor binding and functional are distinctively different. In our quest in finding the novel a4�2 modulators, we have designed and synthesized a series of conformationally constrained pyrrolidine derivatives with favorable ADME properties. The design, synthesis, SAR and pharmacological profile of these novel compounds in animal models of depression will be presented.

Conformationally constrained pyrrolidine derivatives as a4�2 nicotinic acetylcholine receptor ligands and their efficacy in animal models of depression

246th National Meeting (2013)

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