Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.

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Froestl W, Mickel SJ, Hall RG, von Sprecher G, Strub D, Baumann PA, Brugger F, Gentsch C, Jaekel J, Olpe HR, et al.

Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.

J Med Chem. 1995 Aug 18;38(17):3297-312.

PubMed ID
7650684 [ View in PubMed
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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BaclofenGamma-aminobutyric acid type B receptor subunit 1IC 50 (nM)15N/AN/ADetails
BaclofenGamma-aminobutyric acid type B receptor subunit 1IC 50 (nM)35N/AN/ADetails
BaclofenGamma-aminobutyric acid type B receptor subunit 1IC 50 (nM)1770N/AN/ADetails
gamma-Aminobutyric acidGamma-aminobutyric acid type B receptor subunit 1IC 50 (nM)25N/AN/ADetails