(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

Abstract

Gastroesophageal reflux disease (GERD) affects Ͼ10% 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 Ϫ/Ϫ 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.The GABA B receptor was originally defined pharmacologically by virtue of its insensitivity to the GABA A receptor antagonist bicuculline and its sensitivity to the GABA analog baclofen (Bowery et al., 1980). The GABA B receptor, a member of family C of the G protein-coupled receptors, is characterized by its large, ligand-binding extracellular N-terminal domain. It couples negatively to adenylyl cyclase and to voltage-gated calcium channels and positively to inwardly rectifying potassium channels (Bettler et al., 2004).Based on a wealth of preclinical data, the GABA B receptor has been proposed as a therapeutic target for several dis-

Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease

“…GABA-B receptors are located at both central 50, 51 and peripheral [52][53][54][55] sites in the TLOSR reflex arch. Central GABA-B receptors are located in NTS and DMV.…”

“…These studies all point to a reduction in the rate of TLOSRs and of gastrooesophageal reflux. 52,55,[105][106][107][108] A frequently studied GABA-B agonist is baclofen, which not only reduces the rate of TLOSRs, but also has been demonstrated to increase LOS pressure in humans. 52,106 These effects of baclofen contribute to the reduction of gastro-oesophageal reflux in patients with hiatal hernia.…”

“…110, 111 Therefore, more specific, peripherally acting GABA-B agonists are currently being developed that aim to overcome the central side effects. 55,112 A recent study assessed the addition of the more peripherally specific GABA-B agonist lesogaberan to conventional PPI therapy in patients with refractory symptoms and a decrease in reflux events and an increase in LOS pressure was observed. 113 However, some central side effects like headache and paraesthesia may occur when using lesogaberan.…”

Beyond Acid Suppression: New Pharmacologic Approaches for Treatment of GERD

“…Several agents have been identified to reduce the triggering of TLESR, including CCK-A antagonists [9,10], anticholinergic agents [11,12], nitric oxide synthase inhibitors [13], serotonin type 3 (5HT 3 ) antagonists [14], morphine [15], somatostatin [16], N-methyl D-aspartate (NMDA) antagonists [17], and cannabinoid receptor agonist [18•, 19]. However, only γ-aminobutyric type B (GABA(B)) agonists [20,21] and metabotropic glutamate receptor (mGluR) antagonists [22,23] have shown any promise as therapeutic agents.…”

Evaluation of the Pharmacokinetic Interaction between Lesogaberan (AZD3355) and Esomeprazole in Healthy Subjects

“…Conclusions: There was no observed pharmacokinetic interaction between lesogaberan and esomeprazole when concomitantly administered to healthy subjects, and concomitant therapy was well tolerated. Trial registration number (clinicaltrials.gov): NCT00684190 Background GABA B receptor agonists such as lesogaberan (AZD3355) are known to inhibit transient lower esophageal sphincter relaxations, [1] a primary cause of reflux in patients with gastroesophageal reflux disease (GERD). [2] Indeed, pharmacodynamic studies suggest possible therapeutic utility for lesogaberan in patients with persistent GERD symptoms despite proton pump inhibitor (PPI) therapy.…”