Synthesis and evaluation of conformationally restricted pyridino N-alkylated nicotine analogs as nicotinic acetylcholine receptor antagonists

Previous work has shown that quaternization of the pyridine‐N atom of S‐(–)‐nicotine (NIC) affords compounds such as N‐n‐octylnicotinium iodide (NONI) and N‐n‐decylnicotinium iodide (NDNI) that act as competitive nicotinic acetylcholine receptor (nAChR) antagonists at α3β2* and α4β2* subtypes, respectively. To ascertain the rotameric preference about the C3‐C2′ bond of NONI and NDNI for interaction with several nAChR subtypes, two classes of bridged analogs representing extreme rotameric conformations (syn and anti) of NONI and NDNI were synthesized. NIC‐evoked [3H]dopamine ([3H]DA) release from superfused rat striatal slices was used to determine the activity of the analogs at the α3β2* nAChR. [3H]NIC and [3H]methyllycaconitine ([3H]MLA) binding to rat brain membranes were used to determine affinity for α4β2* and α7* nAChRs, respectively. With the exception of BCDD (IC50 value = 1,580 nM), all analogs potently and selectively inhibited NIC‐evoked [3H]DA release (IC50 values = 30–660 nM), indicating antagonism of α3β2* nAChRs. None of the analogs inhibited either [3H]NIC or [3H]MLA binding, indicating a lack of interaction with α4β2* and α7* nAChR subtypes. Interestingly, the C10 N‐alkyl chain analogs, ACD and BCD, had negligible affinity for the α4β2* subtype compared to the high affinity exhibited by NDNI, suggesting that the α4β2* subtype does not recognize the unique stereochemistry of these conformationally restricted analogs. Thus, conformational restriction of N‐n‐alkylnicotinium iodides eliminated inhibitory activity at α4β2* nAChRs, but more importantly afforded high affinity and selectivity for α3β2* nAChRs. Conformational restriction of N‐n‐alkyl analogs of NIC appears to be a viable approach for the development of α3β2*‐selective nAChR antagonists. Drug Dev. Res. 55:172–186, 2002. © 2002 Wiley‐Liss, Inc.