Lehmann Anders, Jensen Jörgen M, Boeckxstaens Guy E
AstraZeneca R&D, Mölndal, Sweden.
Adv Pharmacol. 2010;58:287-313. doi: 10.1016/S1054-3589(10)58012-8.
Defined pharmacologically by its insensitivity to the GABA(A) antagonist bicuculline and sensitivity to the GABA analogue baclofen, the G protein-linked gamma-aminobutyric acid type B (GABA(B)) receptor couples to adenylyl cyclase, voltage-gated calcium channels, and inwardly-rectifying potassium channels. On the basis of a wealth of preclinical data in conjunction with early clinical observations that baclofen improves symptoms of gastroesophageal reflux disease (GERD), the GABA(B) receptor has been proposed as a therapeutic target for a number of diseases including GERD. Subsequently, there has been a significant effort to develop a peripherally-restricted GABA(B) agonist that is devoid of the central nervous system side effects that are observed with baclofen. In this article we review the in vitro and in vivo pharmacology of the peripherally-restricted GABA(B) receptor agonists and the preclinical and clinical development of lesogaberan (AZD3355, (R)-(3-amino-2-fluoropropyl) phosphinic acid), a potent and predominately peripherally-restricted GABA(B) receptor agonist with a preclinical therapeutic window superior to baclofen.
G蛋白偶联的B型γ-氨基丁酸（GABA(B)）受体在药理学上的定义是，它对GABA(A)拮抗剂荷包牡丹碱不敏感，而对GABA类似物巴氯芬敏感，该受体与腺苷酸环化酶、电压门控钙通道和内向整流钾通道偶联。基于大量临床前数据以及巴氯芬可改善胃食管反流病（GERD）症状的早期临床观察结果，GABA(B)受体已被提议作为包括GERD在内的多种疾病的治疗靶点。随后，人们付出了巨大努力来开发一种外周限制型GABA(B)激动剂，该激动剂没有巴氯芬所具有的中枢神经系统副作用。在本文中，我们综述了外周限制型GABA(B)受体激动剂的体外和体内药理学，以及lesogaberan（AZD3355，(R)-(3-氨基-2-氟丙基)次膦酸）的临床前和临床开发情况，lesogaberan是一种强效且主要为外周限制型的GABA(B)受体激动剂，其临床前治疗窗优于巴氯芬。
