Sullivan J P, Donnelly-Roberts D, Briggs C A, Anderson D J, Gopalakrishnan M, Xue I C, Piattoni-Kaplan M, Molinari E, Campbell J E, McKenna D G, Gunn D E, Lin N H, Ryther K B, He Y, Holladay M W, Wonnacott S, Williams M, Arneric S P
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
J Pharmacol Exp Ther. 1997 Oct;283(1):235-46.
Accumulating preclinical and clinical evidence data suggests that compounds that selectively activate neuronal nicotinic acetylcholine receptor (nAChR) subtypes may have therapeutic utility for the treatment of several neurological disorders. In the present study, the in vitro pharmacological properties of the novel cholinergic channel modulator ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine], are described. In radioligand binding studies, ABT-089 was shown to display selectivity toward the high-affinity (-)-cytisine binding site present on the alpha4beta2 nAChR subtype (Ki = 16 nM) relative to the [125I]alpha-bungarotoxin binding site present on the alpha7 (Ki > or = 10,000 nM) and alpha1beta1deltagamma (Ki > 1000 nM) nAChR subtypes. In cation flux and channel current studies, ABT-089 displayed a more complex profile than (-)-nicotine having agonist, partial agonist and inhibitory activities depending on the nAChR subtype with which it interacts. ABT-089 differentially stimulated neurotransmitter release. The compound displayed a similar potency and efficacy to (-)-nicotine to facilitate ACh release (ABT-089, EC50 = 3 microM; (-)-nicotine, EC50 = 1 microM), but was markedly less potent and less efficacious than (-)-nicotine to stimulate dopamine release (ABT-089, EC50 = 1.1 microM; (-)-nicotine, EC50 = 0.04 microM). Additionally, ABT-089 was neuroprotective against the excitotoxic insults elicited by exposure to glutamate in both rat cortical cell cultures (EC50 = 10 +/- 3 microM) and differentiated human IMR32 cells (EC50 = 3 +/- 2 microM). The differential full agonist/partial agonist profile of ABT-089, as compared with (-)-nicotine and ABT-418, illustrates the complexity of nAChR activation and the potential to target responses at subclasses of the neuronal and peripheral receptors.
越来越多的临床前和临床证据数据表明，选择性激活神经元烟碱型乙酰胆碱受体（nAChR）亚型的化合物可能对治疗多种神经系统疾病具有治疗作用。在本研究中，描述了新型胆碱能通道调节剂ABT-089[2-甲基-3-(2-(S)-吡咯烷基甲氧基)吡啶]的体外药理学特性。在放射性配体结合研究中，相对于存在于α7（Ki≥10,000 nM）和α1β1δγ（Ki>1000 nM）nAChR亚型上的[125I]α-银环蛇毒素结合位点，ABT-089显示出对存在于α4β2 nAChR亚型上的高亲和力（-）-金雀花碱结合位点具有选择性（Ki = 16 nM）。在阳离子通量和通道电流研究中，ABT-089表现出比（-）-尼古丁更复杂的特征，根据与其相互作用的nAChR亚型，它具有激动剂、部分激动剂和抑制活性。ABT-089以不同方式刺激神经递质释放。该化合物在促进乙酰胆碱释放方面表现出与（-）-尼古丁相似的效力和效能（ABT-089，EC50 = 3 microM；（-）-尼古丁，EC50 = 1 microM），但在刺激多巴胺释放方面的效力和效能明显低于（-）-尼古丁（ABT-089，EC50 = 1.1 microM；（-）-尼古丁，EC50 = 0.04 microM）。此外，在大鼠皮质细胞培养物（EC50 = 10±3 microM）和分化的人IMR32细胞（EC50 = 3±2 microM）中，ABT-089对谷氨酸暴露引起的兴奋性毒性损伤具有神经保护作用。与（-）-尼古丁和ABT-418相比，ABT-089的差异完全激动剂/部分激动剂特征说明了nAChR激活的复杂性以及针对神经元和外周受体亚类反应的潜力。
