Arneric S P, Sullivan J P, Briggs C A, Donnelly-Roberts D, Anderson D J, Raszkiewicz J L, Hughes M L, Cadman E D, Adams P, Garvey D S
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois.
J Pharmacol Exp Ther. 1994 Jul;270(1):310-8.
A diversity of nicotinic acetylcholine receptor (nAChR) subtypes has been identified in mammalian brain using recombinant DNA technology. Alterations in the activity of these acetylcholinegated ion channels have been implicated in a number of central nervous system disorders including Alzheimer's disease (AD). The potential therapeutic usefulness of (-)-nicotine [(S)-3-(1-methyl-2-pyrrolidinyl) pyridine], the prototypic agonist at nAChRs, is severely limited by side effects that are the result of activation of both cholinergic and noncholinergic pathways in the central and peripheral nervous systems. This study sought to determine the in vitro selectivity of (S)-3-methyl-5-(1methyl-2-pyrrolidinyl)isoxazole (ABT 418), a novel analog of (-)-nicotine in which the pyridine ring was replaced with an isoxazole bioisotere, to activate nAChRs. ABT 418 was a potent inhibitor of [3H]-cytisine binding to nAChR in rat brain (Ki = 3 nM) but was inactive (Ki > 10,000 nM) in 37 other receptor/neurotransmitter-uptake/enzyme/transduction system binding assays, including those for alpha-bungarotoxin, muscarinic and 5-hydroxytryptamine3 receptors. In PC12 cells, patch-clamp studies indicated that ABT 418 was an agonist with an EC50 value of 209 microM, a potency to activate cholinergic channel currents some 4-fold less than that of (-)-nicotine (52 microM). Channel current responses elicited by ABT 418 were prevented by the cholinergic channel blocker, mecamylamine. ABT 418 was also approximately 10-fold less potent (EC50 value = 380 nM) than (-)-nicotine (40 nM) in increasing [3H]-dopamine release from rat striatal slices, an effect that was blocked by the nAChR antagonist, dihydro-beta-erythroidine (10 microM).2+ In contrast, ABT 418 appeared equipotent with (-)-nicotine in enhancing 86Rb+ flux from mouse thalamic synaptosomes. ABT 418 demonstrated an in vitro pharmacological profile of cholinergic channel activation that was robust at some nAChR, but not others. The reasons for this are unclear. However, a nAChR subtype selectivity may account for the in vitro potency differences of ABT 418 on various neurotransmitter systems, and the substantial separation between the cognitive enhancement/anxiolytic benefits, and the reduced central nervous system side-effect liabilities seen in vivo. ABT 418 represents the first neuronal nAChR ligand that differentiates the toxicities/liabilities and other negative aspects normally associated with liabilities and other negative aspects normally associated with (-)-nicotine from the potential pharmacological benefits of selective cholinergic channel activation.
利用重组DNA技术已在哺乳动物大脑中鉴定出多种烟碱型乙酰胆碱受体（nAChR）亚型。这些乙酰胆碱门控离子通道活性的改变与包括阿尔茨海默病（AD）在内的多种中枢神经系统疾病有关。nAChR的原型激动剂（-）-尼古丁[（S）-3-（1-甲基-2-吡咯烷基）吡啶]的潜在治疗用途受到严重限制，因为其副作用是由中枢和外周神经系统中胆碱能和非胆碱能途径的激活所致。本研究旨在确定（S）-3-甲基-5-（1-甲基-2-吡咯烷基）异恶唑（ABT 418）的体外选择性，ABT 418是（-）-尼古丁的一种新型类似物，其中吡啶环被异恶唑生物电子等排体取代，用于激活nAChR。ABT 418是大鼠脑中[3H]-金雀花碱与nAChR结合的有效抑制剂（Ki = 3 nM），但在其他37种受体/神经递质摄取/酶/转导系统结合试验中无活性（Ki > 10,000 nM），包括对α-银环蛇毒素、毒蕈碱和5-羟色胺3受体的试验。在PC12细胞中，膜片钳研究表明ABT 418是一种激动剂，EC50值为209 microM，激活胆碱能通道电流的效力比（-）-尼古丁（52 microM）约低4倍。ABT 418引起的通道电流反应被胆碱能通道阻滞剂美加明阻断。在增加大鼠纹状体切片中[3H]-多巴胺释放方面，ABT 418的效力也比（-）-尼古丁（40 nM）低约10倍（EC50值 = 380 nM），nAChR拮抗剂二氢-β-刺桐碱（10 microM）可阻断这种作用。相比之下，在增强小鼠丘脑突触体的86Rb+通量方面，ABT 418似乎与（-）-尼古丁等效。ABT 418表现出一种胆碱能通道激活的体外药理学特征，在某些nAChR上作用强烈，但在其他nAChR上则不然。其原因尚不清楚。然而，nAChR亚型选择性可能解释了ABT 418在各种神经递质系统上的体外效力差异，以及在体内观察到的认知增强/抗焦虑益处与中枢神经系统副作用减少之间的显著差异。ABT 418是第一种神经元nAChR配体，它将通常与（-）-尼古丁相关的毒性/副作用及其他负面方面与选择性胆碱能通道激活的潜在药理学益处区分开来。
