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.