(R)-(3-amino-2-fluoropropyl) phosphinic acid (AZD3355), a novel GABA B receptor agonist, inhibits transient lower esophageal sphincter relaxation through a peripheral mode of action

Anders Lehmann, Madeleine Antonsson, Ann Aurell Holmberg, L. Ashley Blackshaw, Lena Brändén, Hans Bräuner-Osborne, Bolette Christiansen, John Dent, Thomas Elebring, Britt Marie Jacobson, Jörgen Jensen, Jan P. Mattsson, Karolina Nilsson, Simo S. Oja, Amanda J. Page, Pirjo Saransaari, Sverker Von Unge

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48 Citations (Scopus)

Abstract

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 GABAB receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic acid (AZD3355). AZD3355 potently stimulated recombinant human GABAB receptors and inhibited TLESR in dogs, with a biphasic dose-response curve. In mice, AZD3355 produced considerably less central side effects than the prototypical GABAB receptor agonist baclofen but evoked hypothermia at very high doses (blocked by a GABAB receptor antagonist and absent in GABAB-/- mice). AZD3355 and baclofen 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 GABAB receptors and may offer a potential new approach to treatment of GERD.

Original languageEnglish
Pages (from-to)504-512
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume331
Issue number2
DOIs
Publication statusPublished or Issued - 1 Nov 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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