Phosphinic Acid Analogs of GABA. 1. New Potent and Selective GABAB Agonists

• Published in: Journal of medicinal chemistry Vol. 38; no. 17; pp. 3297 - 3312
• Main Authors: Froestl, Wolfgang, Mickel, Stuart J, Hall, Roger G, von Sprecher, Georg, Strub, Dietrich, Baumann, Peter A, Brugger, Felix, Gentsch, Conrad, Jaekel, Joachim
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.08.1995
• Subjects: Animals; Behavior, Animal - drug effects; Cats; Crystallography, X-Ray; GABA-B Receptor Agonists; gamma-Aminobutyric Acid - analogs & derivatives; gamma-Aminobutyric Acid - pharmacology; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Organophosphonates - chemistry; Organophosphonates - pharmacology; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, GABA-B - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00017a015

The antispastic agent and muscle relaxant baclofen 1 is a potent and selective agonist for bicuculline-insensitive GABAB receptors. For many years efforts to obtain superior GABAB agonists were unsuccessful. We describe the syntheses and biological properties of two new series of GABAB agonists, the best compounds of which are more potent than baclofen in vitro and in vivo. They were obtained by replacing the carboxylic acid group of GABA or baclofen derivatives with either the phosphinic acid or the methylphosphinic acid residue. Surprisingly, ethyl- and higher alkylphosphinic acid derivatives of GABA yielded novel GABAB antagonists, which are described in part 2 of this series. Structure-activity relationships of the novel GABAB agonists are discussed with respect to their affinities to GABAB receptors as well as to their effects in many functional tests in vitro and in vivo providing new muscle relaxant drugs with significantly improved side effect profiles.