GABAB receptor agonism as a novel therapeutic modality in the treatment of gastroesophageal reflux disease.

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.