Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABA_B) Receptor Agonists as Gastroesophageal Reflux Inhibitors

Abstract

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.

Reducing Adverse Effects During Drug Development: The Example of Lesogaberan and Paresthesia

“…Other selective GA-BA B agonists (AZD9343 and baclofen) are associated with paresthesia in humans but to a lesser degree. 15,16 This finding is consistent with the lower potency of these molecules in terms of GABA B activation compared with lesogaberan, although baclofen tablets also do not cause the rapid increase in plasma concentrations seen after dosing with a lesogaberan solution. 16 In addition, scratching behavior was assessed in dogs after administration of lesogaberan (7.5 mg/kg) compared with placebo (saline vehicle) based on the hypothesis that this action would be a behavioral response to paresthesia.…”

Synthesis and Biological Applications of Phosphinates and Derivatives

“…For that purpose, he decided to explore derivatives of 3-aminopropylphosphinic acid 59 (R 1 ¼ R 2 ¼ H), which has been demonstrated to be a potent and selective GABA B agonist [67] (Fig. 11).…”

(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

“…As a consequence, research efforts have focused on GABA B receptor agonists with minimal side effects. Here, we characterize the in vitro and in vivo pharmacology of AZD3355 (Alstermark et al, 2008), a potent and selective GABA B receptor agonist with a preclinical therapeutic window superior to baclofen.…”