Froestl Wolfgang
AC Immune SA, Lausanne, Switzerland.
Adv Pharmacol. 2010;58:19-62. doi: 10.1016/S1054-3589(10)58002-5.
This chapter presents new clinical applications of the prototypic GABA(B) receptor agonist baclofen for the treatment of addiction by drugs of abuse, such as alcohol, cocaine, nicotine, morphine, and heroin, a novel baclofen prodrug Arbaclofen placarbil, the GABA(B) receptor agonist AZD3355 (Lesogabaran) currently in Phase 2 clinical trials for the treatment of gastroesophageal reflux disease, and four positive allosteric modulators of GABA(B) receptors (CGP7930, GS39783, NVP-BHF177, and BHFF), which have less propensity for the development of tolerance due to receptor desensitization than classical GABA(B) receptor agonists. All four compounds showed anxiolytic affects. In the presence of positive allosteric modulators the "classical" GABA(B) receptor antagonists CGP35348 and 2-hydroxy-saclofen showed properties of partial GABA(B) receptor agonists. Seven micromolar affinity GABA(B) receptor antagonists, phaclofen; 2-hydroxy-saclofen; CGP's 35348, 36742, 46381, 51176; and SCH50911, are discussed. CGP36742 (SGS742) showed statistically significant improvements of working memory and attention in a Phase 2 clinical trial in mild, but not in moderate Alzheimer patients. Eight nanomolar affinity GABA(B) receptor antagonists are presented (CGP's 52432, 54626, 55845, 56433, 56999, 61334, 62349, and 63360) that were used by pharmacologists for numerous in vitro and in vivo investigations. CGP's 36742, 51176, 55845, and 56433 showed antidepressant effects. Several compounds are also available as radioligands, such as [(3)H]CGP27492, [(3)H]CGP54626, [(3)H]CGP5699, and [(3)H]CGP62349. Three novel fluorescent and three GABA(B) receptor antagonists with very high specific radioactivity (>2,000 Ci/mmol) are presented. [(125)I]CGP64213 and the photoaffinity ligand [(125)I]CGP71872 allowed the identification of GABA(B1a) and GABA(B1b) receptors in the expression cloning work.
本章介绍了原型γ-氨基丁酸B（GABA(B)）受体激动剂巴氯芬在治疗成瘾性药物（如酒精、可卡因、尼古丁、吗啡和海洛因）成瘾方面的新临床应用，一种新型巴氯芬前药阿巴氯芬普拉卡比尔，目前正在进行治疗胃食管反流病的2期临床试验的GABA(B)受体激动剂AZD3355（来索加巴兰），以及四种GABA(B)受体的正变构调节剂（CGP7930、GS39783、NVP-BHF177和BHFF），与经典GABA(B)受体激动剂相比，它们因受体脱敏而产生耐受性的倾向较小。所有这四种化合物均显示出抗焦虑作用。在正变构调节剂存在的情况下，“经典”GABA(B)受体拮抗剂CGP35348和2-羟基-巴氯芬表现出部分GABA(B)受体激动剂的特性。讨论了七种具有微摩尔亲和力的GABA(B)受体拮抗剂，即法氯芬、2-羟基-巴氯芬、CGP的35348、36742、46381、51176以及SCH50911。CGP36742（SGS742）在一项针对轻度但非中度阿尔茨海默病患者的2期临床试验中显示出工作记忆和注意力的统计学显著改善。介绍了八种具有纳摩尔亲和力的GABA(B)受体拮抗剂（CGP的52432、54626、55845、56433、56999、61334、62349和63360），药理学家将其用于众多体外和体内研究。CGP的36742、51176、55845和56433显示出抗抑郁作用。还有几种化合物可作为放射性配体，如[(3)H]CGP27492、[(3)H]CGP54626、[(3)H]CGP5699和[(3)H]CGP62349。介绍了三种新型荧光和三种具有非常高比放射性（>2,000 Ci/mmol）的GABA(B)受体拮抗剂。[(125)I]CGP64213和光亲和配体[(125)I]CGP71872在表达克隆工作中有助于鉴定GABA(B1a)和GABA(B1b)受体。
