Discovery of a novel potent GABAB receptor agonist

Structure–activity studies have led to a discovery of 3-(4-pyridyl)methyl ether derivative 9d that has 25- to 50-fold greater functional potency than R-baclofen at human and rodent GABAB receptors in vitro. Mouse hypothermia studies confirm that this compound crosses the blood–brain barrier and is approximately 50-fold more potent after systemic administration.

Graphical abstractNovel substituted analogs or R-baclofen was explored and a highly potent agonist was discovered. (9d pEC50 = 8.5). Characterization of 9d showed it to be 25- to 50-fold more potent than R-baclofen in vitro and in vivo.Figure optionsDownload full-size imageDownload as PowerPoint slide