NOVEL 2-(2'-FURO[3,2-B]PYRIDINYL) PYRROLIDINES - POTENT NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTOR LIGANDS

A novel series of 2-(2'-furo[3,2-b]pyridinyl) pyrrolidines has been sy nthesized and evaluated as novel nicotinic acetylcholine receptor liga nds. Changing the pyrrolidine stereochemistry and N-substitution patte rn afforded analogs with K-i values ranging from 2.7 to 97 nM. Rubidiu m efflux studies revealed that these compounds had intrinsic activitie s ranging from 9-58% that of nicotine in the IMR-32 cell line and 6-81 % in the K177 cell line. The N(Me)-2(S) analog 3a demonstrated good se lectivity in the K177 cell line (alpha(4) beta(2) receptor) versus the IMR-32 cells (alpha(3) beta(x) receptor) and TE 671 cells (alpha(1) n euromuscular receptor), and was a partial agonist with an EC50 value o f 141 nM in dopamine release assay using rat striatal slices. (C) 1997 Elsevier Science Ltd.