(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

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

doi:10.1124/jpet.109.153593

(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

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 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.

Original language	English
Journal	Journal of Pharmacology and Experimental Therapeutics
Volume	331
Issue number	2
Pages (from-to)	504-512
ISSN	0022-3565
DOIs	https://doi.org/10.1124/jpet.109.153593
Publication status	Published - 2009

Keywords

Former Faculty of Pharmaceutical Sciences

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1124/jpet.109.153593

Cite this

Lehmann, A., Antonsson, M., Holmberg, A. A., Blackshaw, L. A., Brändén, L., Bräuner-Osborne, H., Christiansen, B., Dent, J., Elebring, T., Jacobson, B-M., Jensen, J., Mattsson, J. P., Nilsson, K., Oja, S. S., Page, A. J., Saransaari, P., & von Unge, S. (2009). (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. Journal of Pharmacology and Experimental Therapeutics, 331(2), 504-512. https://doi.org/10.1124/jpet.109.153593

(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. / Lehmann, Anders; Antonsson, Madeleine; Holmberg, Ann Aurell et al.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 331, No. 2, 2009, p. 504-512.

Research output: Contribution to journal › Journal article › Research › peer-review

Lehmann, A, Antonsson, M, Holmberg, AA, Blackshaw, LA, Brändén, L, Bräuner-Osborne, H, Christiansen, B, Dent, J, Elebring, T, Jacobson, B-M, Jensen, J, Mattsson, JP, Nilsson, K, Oja, SS, Page, AJ, Saransaari, P & von Unge, S 2009, '(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', Journal of Pharmacology and Experimental Therapeutics, vol. 331, no. 2, pp. 504-512. https://doi.org/10.1124/jpet.109.153593

Lehmann A, Antonsson M, Holmberg AA, Blackshaw LA, Brändén L, Bräuner-Osborne H et al. (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. Journal of Pharmacology and Experimental Therapeutics. 2009;331(2):504-512. doi: 10.1124/jpet.109.153593

@article{24fb28e0c46e11debda0000ea68e967b,

title = "(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",

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 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.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Anders Lehmann and Madeleine Antonsson and Holmberg, {Ann Aurell} and Blackshaw, {L. Ashley} and Lena Br{\"a}nd{\'e}n and Hans Br{\"a}uner-Osborne and Bolette Christiansen and John Dent and Thomas Elebring and Britt-Marie Jacobson and J{\"o}rgen Jensen and Mattsson, {Jan P.} and Karolina Nilsson and Oja, {Simo S.} and Page, {Amanda J.} and Pirjo Saransaari and {von Unge}, Sverker",

year = "2009",

doi = "10.1124/jpet.109.153593",

language = "English",

volume = "331",

pages = "504--512",

journal = "Journal of Pharmacology and Experimental Therapeutics",

issn = "0022-3565",

publisher = "American Society for Pharmacology and Experimental Therapeutics",

number = "2",

}

TY - JOUR

T1 - (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

AU - Lehmann, Anders

AU - Antonsson, Madeleine

AU - Holmberg, Ann Aurell

AU - Blackshaw, L. Ashley

AU - Brändén, Lena

AU - Bräuner-Osborne, Hans

AU - Christiansen, Bolette

AU - Dent, John

AU - Elebring, Thomas

AU - Jacobson, Britt-Marie

AU - Jensen, Jörgen

AU - Mattsson, Jan P.

AU - Nilsson, Karolina

AU - Oja, Simo S.

AU - Page, Amanda J.

AU - Saransaari, Pirjo

AU - von Unge, Sverker

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1124/jpet.109.153593

DO - 10.1124/jpet.109.153593

M3 - Journal article

C2 - 19648470

SN - 0022-3565

VL - 331

SP - 504

EP - 512

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

IS - 2

ER -