Novel g-aminobutyric acid r1 receptor antagonists; synthesis, pharmacological activity and structure-activity relationships.

[摘要]：g-Aminobutyric acid (GABA) phosphinic acid analogs, (4-amino-1-cyclopenten-1-yl)-R-phosphinic acids (34-42; R = Me, Et, iPr, Bu, PhCH2), (3-amino-1-hydroxycyclobutyl)(methyl)phosphinic acids (51, 52) and (3-aminocyclobutyl)(methyl)phosphinic acids (56, 57) were prepd. and for their investigated for their homomeric r1 GABAC receptor antagonist activity. The effect of the stereochem. and phosphinic acid substituent of these compds. on potency and selectivity within the GABA receptor subtypes was investigated. Compds. of high potency at GABAC r1 receptors (36, KB = 0.78 mM) and selectivity greater than 100 times (41, KB = 4.97 mM) were obtained. The data obtained was analyzed along with the known set of GABAC r1 receptor-ligands, leading to the development of a pharmacophore model for this receptor, which can be used for in silico screening.

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