Introduction of unsaturation into the N-n-Alkyl chain of the nicotinic receptor antagonists, NONI and NDNI: Effect on affinity and selectivity

N-n-Octylnicotinium iodide (NONI) and N-n-decylnicotinium iodide (NDNI) are selective nicotinic receptor (nAChR) antagonists mediating nicotine-evoked striatal dopamine (DA) release, and inhibiting [³H]nicotine binding, respectively. This study evaluated effects of introducing unsaturation into the N-n-alkyl chains of NONI and NDNI on inhibition of [³H]nicotine and [³H]methyllycaconitine binding (α4β2* and α7* nAChRs, respectively), ⁸⁶Rb⁺ efflux and [³H]DA release (agonist or antagonist effects at α4β2* and α6β2*-containing nAChRs, respectively). In the NONI series, introduction of a C₃-cis- (NONB3c), C₃-trans-(NONB3t), C₇-double-bond (NONB7e), or C₃-triple-bond (NONB3y) afforded a 4-fold to 250-fold increased affinity for [³H]nicotine binding sites compared with NONI. NONB7e and NONB3y inhibited nicotine-evoked ⁸⁶Rb⁺ efflux, indicating α4β2* antagonism. NONI analogs exhibited a 3-fold to 8-fold greater potency inhibiting nicotine-evoked [³H]DA overflow compared with NONI (IC₅₀ = 0.62 μM; Imax = 89%), with no change in Imax, except for NONB3y (Imax = 50%). In the NDNI series, introduction of a C₄-cis- (NDNB4c), C₄-trans-double-bond (NDNB4t), or C₃-triple-bond (NDNB3y) afforded a 4-fold to 80-fold decreased affinity for [³H]nicotine binding sites compared with NDNI, whereas introduction of a C₉ double-bond (NDNB9e) did not alter affinity. NDNB3y and NDNB4t inhibited nicotine-evoked ⁸⁶Rb⁺ efflux, indicating antagonism at α4β2* nAChRs. Although NDNI had no effect, NDNB4t and NDNB9e potently inhibited nicotine-evoked [³H]DA overflow (IC₅₀ = 0.02-0.14 μM, Imax = 90%), as did NDNB4c (IC₅₀ = 0.08 μM; Imax = 50%), whereas NDNB3y showed no inhibition. None of the analogs had significant affinity for α7* nAChRs. Thus, unsaturated NONI analogs had enhanced affinity at α4β2*- and α6β2*-containing nAChRs, however a general reduction of affinity at α4β2* and an uncovering of antagonist effects at α6β2*-containing nAChRs were observed with unsaturated NDNI analogs.