Mullen G, Napier J, Balestra M, DeCory T, Hale G, Macor J, Mack R, Loch J, Wu E, Kover A, Verhoest P, Sampognaro A, Phillips E, Zhu Y, Murray R, Griffith R, Blosser J, Gurley D, Machulskis A, Zongrone J, Rosen A, Gordon J
Department of Chemistry, AstraZeneca R&D Boston, 3 Biotech, One Innovation Drive, Worcester, Massachusetts 01605, USA.
J Med Chem. 2000 Nov 2;43(22):4045-50. doi: 10.1021/jm000249r.
Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.
神经元烟碱型乙酰胆碱受体是配体门控离子通道受体超家族的成员，可能在调节神经传递、认知、感觉门控和焦虑方面发挥重要作用。由于α7烟碱受体在中枢神经系统中的分布和丰度，它很可能参与其中一些功能。在本文中，我们描述了AR-R17779，（-）-螺[1-氮杂双环[2.2.2]辛烷-3,5'-恶唑烷-2'-酮]（4a）的合成及其体外特性，它是大鼠α7烟碱受体的强效完全激动剂，对大鼠α7烟碱受体的选择性远高于α4β2亚型。本文给出的AR-R17779的初步构效关系表明，对这个刚性分子进行修饰的空间很小，因为即使是微小的变化也会导致α7烟碱受体亲和力的显著丧失。
