(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.
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.
Lehmann
Anders
A
AstraZeneca R&D, Mölndal, Sweden. anders.lehmann@astrazeneca.com
Antonsson
Madeleine
M
Holmberg
Ann Aurell
AA
Blackshaw
L Ashley
LA
Brändén
Lena
L
Bräuner-Osborne
Hans
H
Christiansen
Bolette
B
Dent
John
J
Elebring
Thomas
T
Jacobson
Britt-Marie
BM
Jensen
Jörgen
J
Mattsson
Jan P
JP
Nilsson
Karolina
K
Oja
Simo S
SS
Page
Amanda J
AJ
Saransaari
Pirjo
P
von Unge
Sverker
S
D000818:Animals; D001345:Autoradiography; D001418:Baclofen / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D049630:Esophageal Sphincter, Lower / Q000187:drug effects* / Q000294:innervation; D005260:Female; D005289:Ferrets / Q000378:metabolism; D018755:GABA Agonists / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D058786:GABA-B Receptor Agonists; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects*; D010721:Phosphinic Acids / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D018755:GABA Agonists; D050485:GABA Plasma Membrane Transport Proteins; D058786:GABA-B Receptor Agonists; D010721:Phosphinic Acids; D011437:Propylamines; D020033:Protein Isoforms; D018080:Receptors, GABA-B; C545087:lesogaberan; D001418:Baclofen; D002118:Calcium