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