Introduction of unsaturation into theN-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 [ 3 H]nicotine binding, respectively. This study evaluated effects of introducing unsaturation into the N-n -alkyl chains of NONI and NDNI on inhibition of [ 3 H]nicotine and [ 3 H]methyllycaconitine binding (α4β2* and α7* nAChRs, respectively), 86 Rb + efflux and [ 3 H]DA release (agonist or antagonist effects at α4β2* and α6β2*-containing nAChRs, respectively). In the NONI series, introduction of a C 3 - cis -(NONB3c), C 3 - trans -(NONB3t), C 7 -double-bond (NONB7e), or C 3 -triple-bond (NONB3y) afforded a 4-fold to 250-fold increased affinity for [ 3 H]nicotine binding sites compared with NONI. NONB7e and NONB3y inhibited nicotine-evoked 86 Rb + efflux, indicating α4β2* antagonism. NONI analogs exhibited a 3-fold to 8-fold greater potency inhibiting nicotine-evoked [ 3 H]DA overflow compared with NONI (IC 50 =0.62 μM; Imax=89%), with no change in Imax, except for NONB3y (Imax=50%). In the NDNI series, introduction of a C 4 - cis -(NDNB4c), C 4 - trans -double-bond (NDNB4t), or C 3 -triple-bond (NDNB3y) afforded a 4-fold to 80-fold decreased affinity for [ 3 H]nicotine binding sites compared with NDNI, whereas introduction of a C 9 -double-bond (NDNB9e) did not alter affinity. NDNB3y and NDNB4t inhibited nicotine-evoked 86 Rb + efflux, indicating anatogonism at α4β2* nAChRs. Although NDNI had no effect, NDNB4t and NDNB9e potently inhibited nicotine-evoked [ 3 H]DA overflow (IC 50 =0.02–0.14μM, Imax=90%), as did NDNB4c (IC 50 =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.