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Unsaturated phosphinic analogues of γ-aminobutyric acid as GABAC receptor antagonists

1997; Elsevier BV; Volume: 329; Issue: 2-3 Linguagem: Inglês

10.1016/s0014-2999(97)89183-2

1879-0712

Mary Chebib, Robert J. Vandenberg, Wolfgang Froestl, Graham A.R. Johnston,

Organophosphorus compounds synthesis

The phosphinic and methylphosphinic analogues of γ-aminobutyric acid (GABA) are potent GABAC receptor antagonists but are even more potent as GABAB receptor agonists. Conformationally restricted unsaturated phosphinic and methylphosphinic analogues of GABA and some potent GABAB receptor phosphonoamino acid antagonists were tested on GABAC receptors in Xenopus oocytes expressing human retinal ϱ1 mRNA. 3-Aminopropyl-n-butyl-phosphinic acid (CGP36742), an orally active GABAB receptor antagonist, was found to be a moderately potent GABAC receptor antagonist (IC50 = 62 μM). The unsaturated methylphosphinic and phosphinic analogues of GABA were competitive antagonists of the GABAC receptors, the order of potency being [(E)-3-aminopropen-1-yl]methyl-phosphinic acid (CGP44530, IC50 = 5.53 μM) > [(E)-3-aminopropen-1-yl]phosphinic acid (CGP38593, IC50 = 7.68 μM) > [(Z)-3-aminopropen-1-yl]methylphosphinic acid (CGP70523, IC50 = 38.94 μM) > [(Z)-3-aminopropen-1-yl]phosphinic acid (CGP70522, IC50 > 100 μM). This order of potency differs from that reported for these compounds as GABAB receptor agonists, where the phosphinic acids are more potent than the corresponding methylphosphinic acids.