Tatsumi Ryo, Fujio Masakazu, Satoh Hiroyuki, Katayama Jiro, Takanashi Shin-Ichi, Hashimoto Kenji, Tanaka Hiroshi
Pharmaceuticals Research Unit, Research & Development Division, Mitsubishi Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
J Med Chem. 2005 Apr 7;48(7):2678-86. doi: 10.1021/jm049188d.
Recent advances in molecular biology suggest that neuronal nicotinic acetylcholine receptors play important roles in the central nervous system (CNS). Of these receptors, the alpha7 group has recently attracted interest for its CNS-related actions and is looked to as a potential new class of pharmacological targets for cognition, schizophrenia, sensory gating, and anxiety. In the course of a research program aimed at the discovery of alpha7 receptor agonists with high affinity, subtype selectivity, and good pharmacokinetic profile, we discovered (R)-3'-(5-chlorothiophen-2-yl)spiro-1-azabicyclo[2.2.2]octane-3,5'-[1',3']oxazolidin-2'-one (25). Compound 25 has potent binding affinity (K(i) = 9 nmol/L) and good selectivity toward the other nicotinic subtypes (alpha4beta2 and alpha1beta2gammadelta) and has been found in pharmacokinetic evaluation to have good oral bioavailability and brain permeability.
分子生物学的最新进展表明，神经元烟碱型乙酰胆碱受体在中枢神经系统（CNS）中发挥着重要作用。在这些受体中，α7组最近因其与中枢神经系统相关的作用而受到关注，并有望成为一类潜在的用于认知、精神分裂症、感觉门控和焦虑症的新型药理学靶点。在一项旨在发现具有高亲和力、亚型选择性和良好药代动力学特征的α7受体激动剂的研究项目过程中，我们发现了（R）-3'-（5-氯噻吩-2-基）螺-1-氮杂双环[2.2.2]辛烷-3,5'-[1',3']恶唑烷-2'-酮（25）。化合物25具有强大的结合亲和力（K(i)=9 nmol/L），对其他烟碱型亚型（α4β2和α1β2γδ）具有良好的选择性，并且在药代动力学评估中发现其具有良好的口服生物利用度和脑通透性。
