Journal of Medicinal Chemistry 1985-09-01

Structure-activity relationships of some pyridine, piperidine, and pyrrolidine analogues for enhancing and inhibiting the binding of (+/-)-[3H]nicotine to the rat brain P2 preparation.

J W Sloan, W R Martin, R Hook, J Hernandez

Index: J. Med. Chem. 28(9) , 1245-51, (1985)

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Abstract

Previous studies have shown that (+/-)-[3H]nicotine binds to multiple sites in the rat brain P2 preparation. Using a series of pyridine, piperidine and pyrrolidine analogues, the present studies identified drugs with specificity for a separate up-regulatory site that increases the density of nicotine binding at another site. Of these compounds, (+/-)-2-methylpiperidine was the most specific. Some compounds inhibited without enhancing (+/-)-[3H]nicotine binding, but none bound with the very high affinity exhibited by nicotine and none could be classified as specific in inhibiting binding at a specific site. Structural changes in the 1- and 2-positions of pyridine and piperidine appear to be important for conferring specificity for the up-regulatory site whereas 3-position changes may be important for binding specificity.