2-HALO-3-(2(S)-AZETIDINYLMETHOXY)PYRIDINES, 5-HALO-3-(2(S)-AZETIDINYLMETHOXY)PYRIDINES, AND 6-HALO-3-(2(S)-AZETIDINYLMETHOXY)PYRIDINES - SYNTHESIS, AFFINITY FOR NICOTINIC ACETYLCHOLINE-RECEPTORS, AND MOLECULARMODELING

3-(2(S)-Azetidinylmethoxy)pyridine (A-85380) has been identified recen tly as a ligand with high affinity for nicotinic acetylcholine recepto rs (nAChRs). Here we report the synthesis and in vitro nAChR binding o f a series of 10 pyridine-modified analogues of A-85380; The novel com pounds feature a halogen substituent at position 2, 5, or 6 of the 3-p yridyl fragment. Those with the substituents at position 5 or 6, as we ll as the 2-fluoro analogue, possess subnanomolar affinity for nAChRs in membranes from rat brain. For these ligands, K-i values range from 11 to 210 pM, as measured by competition with (+/-)-[H-3]epibatidine. In contrast, 2-chloro, 2-bromo, and 2-iodo analogues exhibit substanti ally lower affinity. AM1 quantum chemical calculations demonstrate tha t the bulky substituents at position 2 cause notable changes in the mo lecular geometry. The high-affinity members of the series and (+)-epib atidine display a tight fit superposition of low-energy stable conform ers. The new ligands with high affinity for nAChRs may be of interest as pharmacological probes, potential medications, and candidates for d eveloping radiohalogenated tracers to study nAChRs.