(R)-(3-Amino-2-fluoropropyl) Phosphinic Acid (AZD3355), a Novel GABAB Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxation through a Peripheral Mode of Action

摘要: Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which effective in most patients but inadequate a significant minority. We describe new therapeutic approach for GERD, based on inhibition transient lower esophageal sphincter relaxation (TLESR) with proposed peripherally acting GABA(B) receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic (AZD3355). AZD3355 potently stimulated recombinant human receptors and inhibited TLESR dogs, biphasic dose-response curve. In mice, produced considerably less central side effects than prototypical agonist baclofen evoked hypothermia at very high doses (blocked antagonist absent GABA(B)-/- mice). differed markedly their distribution rat brain; AZD3355, not baclofen, was concentrated circumventricular organs as result active uptake (shown avid intracellular sequestration) related to binding native GABA transporters cerebrocortical membranes. also shown be transported all four transporters. AR-H061719 [(R/S)-(3-amino-2-fluoropropyl)phosphinic acid], (the racemate AZD3355) response ferret mechanoreceptors distension, further supporting its peripheral site action TLESR. summary, probably inhibits through stimulation may offer potential treatment GERD.