(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

被引：34

作者：

Lehmann, Anders ^{[1
]}

Antonsson, Madeleine ^{[1
]}

Holmberg, Ann Aurell ^{[1
]}

Blackshaw, L. Ashley ^{[2
,3
]}

Branden, Lena ^{[1
]}

Braeuner-Osborne, Hans ^{[4
]}

Christiansen, Bolette ^{[4
]}

Dent, John ^{[2
,3
]}

Elebring, Thomas ^{[1
]}

Jacobson, Britt-Marie ^{[1
]}

Jensen, Jorgen ^{[1
]}

Mattsson, Jan P. ^{[1
]}

Nilsson, Karolina ^{[1
]}

Oja, Simo S. ^{[5
]}

Page, Amanda J. ^{[2
,3
]}

Saransaari, Pirjo ^{[6
]}

von Unge, Sverker ^{[1
]}

机构：

[1] AstraZeneca R&D, SE-43183 Molndal, Sweden

[2] Royal Adelaide Hosp, Dept Gastroenterol & Hepatol, Hanson Inst, Adelaide, SA 5000, Australia

[3] Univ Adelaide, Adelaide, SA, Australia

[4] Univ Copenhagen, Dept Med Chem, Fac Pharmaceut Sci, Copenhagen, Denmark

[5] Tampere Univ Hosp, Dept Paediat, Tampere, Finland

[6] Tampere Univ Hosp, Sch Med, Brain Res Ctr, Tampere, Finland

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2009年 / 331卷 / 02期

基金：

英国医学研究理事会;

关键词：

GASTROESOPHAGEAL-REFLUX DISEASE; GAMMA-AMINOBUTYRATE; LES RELAXATIONS; BACLOFEN; SYMPTOMS; RELEASE; DOGS; MECHANOSENSITIVITY; TRANSPORTER; PATHWAYS;

D O I：

10.1124/jpet.109.153593

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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-2fluoropropyl)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.

引用

页码：504 / 512

页数：9

共 36 条

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