Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors

J Med Chem. 2008 Jul 24;51(14):4315-20. doi: 10.1021/jm701425k. Epub 2008 Jun 25.


We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • GABA Agonists / chemistry*
  • GABA Agonists / pharmacology*
  • GABA Agonists / therapeutic use
  • GABA-B Receptor Agonists*
  • Gastroesophageal Reflux / drug therapy*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Spectrometry, Mass, Fast Atom Bombardment


  • GABA Agonists
  • GABA-B Receptor Agonists