Novel gamma-aminobutyric acid rho1 receptor antagonists; synthesis, pharmacological activity and structure-activity relationships.

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Kumar RJ, Chebib M, Hibbs DE, Kim HL, Johnston GA, Salam NK, Hanrahan JR

Novel gamma-aminobutyric acid rho1 receptor antagonists; synthesis, pharmacological activity and structure-activity relationships.

J Med Chem. 2008 Jul 10;51(13):3825-40. doi: 10.1021/jm7015842. Epub 2008 Jun 5.

PubMed ID

18528996 [ View in PubMed

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Abstract

Gamma-aminobutyric acid (GABA) analogues based on 4-amino-cyclopent-1-enyl phosphinic acid ( 34- 42) and 3-aminocyclobutane phosphinic acids ( 51, 52, 56, 57) were investigated in order to obtain selective homomeric rho 1 GABA C receptor antagonists. The effect of the stereochemistry and phosphinic acid substituent of these compounds on potency and selectivity within the GABA receptor subtypes was investigated. Compounds of high potency at GABA C rho 1 receptors ( 36, K B = 0.78 microM) and selectivity greater than 100 times ( 41, K B = 4.97 microM) were obtained. The data obtained was analyzed along with the known set of GABA C rho 1 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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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
gamma-Aminobutyric acid	Gamma-aminobutyric acid type B receptor subunit 1	EC 50 (nM)	1700	N/A	N/A	Details