Novel nicotinic receptor ligands

Few agents (agonists) bind at [3H]nicotine-labeled nicotine receptors with an affinity comparable to that of nicotine. We initially approached this problem by undertaking a systematic structure-affinity study to determine the contribution to binding of various aspects of the nicotine molecule and of nicotine-related derivatives. For example a series of aryl-substituted and unsubstituted, primary, secondary, and tertiary amine derivatives of 3-(aminomethyl)pyridine (1) were prepared and examined. The finding that 1 (R = Me, R’ = Et, X = H) binds with good affinity (Ki = 28 nM) led to the synthesis of several conformationally-restricted analogs, such as 2 and 3 (Ki = 85 and 12 nM, respectively). With the availability of such structure-affinity and conformational data, it should now be possible to optimize affintiy by design and synthesis of new compounds. (Supported in part by funding from TDC/CIT.)