Sumithran Sangeetha P, Crooks Peter A, Xu Rui, Zhu Jun, Deaciuc Agripina G, Wilkins Lincoln H, Dwoskin Linda P
College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
AAPS J. 2005 Aug 29;7(1):E201-17. doi: 10.1208/aapsj070119.
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 (alpha4beta2* and alpha7* nAChRs, respectively), (86)Rb+ efflux and [3H]DA release (agonist or antagonist effects at alpha4beta2* and alpha6beta2*-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 alpha4beta2* antagonism. NONI analogs exhibited a 3-fold to 8-fold greater potency inhibiting nicotine-evoked [3H]DA overflow compared with NONI (IC50 = 0.62 microM; 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 alpha4beta2* nAChRs. Although NDNI had no effect, NDNB4t and NDNB9e potently inhibited nicotine-evoked [3H]DA overflow (IC50 = 0.02-0.14 microM, Imax = 90%), as did NDNB4c (IC50 = 0.08 microM; Imax = 50%), whereas NDNB3y showed no inhibition. None of the analogs had significant affinity for alpha7* nAChRs. Thus, unsaturated NONI analogs had enhanced affinity at alpha4beta2*- and alpha6beta2*-containing nAChRs, however a general reduction of affinity at alpha4beta2* and an uncovering of antagonist effects at alpha6beta2*-containing nAChRs were observed with unsaturated NDNI analogs.
碘化N - 正辛基烟碱（NONI）和碘化N - 正癸基烟碱（NDNI）分别是选择性烟碱受体（nAChR）拮抗剂，介导尼古丁诱发的纹状体多巴胺（DA）释放，并分别抑制[3H]尼古丁结合。本研究评估了在NONI和NDNI的N - 正烷基链中引入不饱和键对抑制[3H]尼古丁和[3H]甲基lycaconitine结合（分别为α4β2和α7 nAChRs）、（86）Rb+外流以及[3H]DA释放（分别为对含α4β2和α6β2的nAChRs的激动剂或拮抗剂作用）的影响。在NONI系列中，引入C3 - 顺式 - （NONB3c）、C3 - 反式 - （NONB3t）、C7 - 双键（NONB7e）或C3 - 三键（NONB3y）后，与NONI相比，对[3H]尼古丁结合位点的亲和力提高了4倍至250倍。NONB7e和NONB3y抑制尼古丁诱发的86Rb+外流，表明具有α4β2拮抗剂作用。NONI类似物抑制尼古丁诱发的[3H]DA溢出的效力比NONI高3倍至8倍（IC50 = 0.62 microM；Imax = 89%），除了NONB3y（Imax = 50%）外，Imax没有变化。在NDNI系列中，引入C4 - 顺式 - （NDNB4c）、C4 - 反式 - 双键（NDNB4t）或C3 - 三键（NDNB3y）后，与NDNI相比，对[3H]尼古丁结合位点的亲和力降低了4倍至80倍，而引入C9双键（NDNB9e）则不改变亲和力。NDNB3y和NDNB4t抑制尼古丁诱发的86Rb+外流，表明对α4β2 nAChRs具有拮抗作用。虽然NDNI没有作用，但NDNB4t和NDNB9e有效抑制尼古丁诱发的[3H]DA溢出（IC50 = 0.02 - 0.14 microM，Imax = 90%），NDNB4c也是如此（IC50 = 0.08 microM；Imax = 50%），而NDNB3y没有抑制作用。这些类似物对α7* nAChRs均无显著亲和力。因此，不饱和NONI类似物在含α4β2和α6β2的nAChRs上具有增强的亲和力，然而，不饱和NDNI类似物则观察到在α4β2上亲和力普遍降低，以及在含α6β2的nAChRs上出现拮抗剂作用。
