Kumar Rohan J, Chebib Mary, Hibbs David E, Kim Hye-Lim, Johnston Graham A R, Salam Noeris K, Hanrahan Jane R
Faculty of Pharmacy, University of Sydney, NSW, Australia.
J Med Chem. 2008 Jul 10;51(13):3825-40. doi: 10.1021/jm7015842. Epub 2008 Jun 5.
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.
为了获得选择性同聚rho 1 GABA C受体拮抗剂，对基于4-氨基环戊-1-烯基次膦酸（34 - 42）和3-氨基环丁烷次膦酸（51、52、56、57）的γ-氨基丁酸（GABA）类似物进行了研究。研究了这些化合物的立体化学和次膦酸取代基对GABA受体亚型内效价和选择性的影响。获得了对GABA C rho 1受体具有高效价（36，K B = 0.78 microM）且选择性大于100倍（41，K B = 4.97 microM）的化合物。将获得的数据与已知的GABA C rho 1受体配体组一起进行分析，从而开发出该受体的药效团模型，可用于计算机模拟筛选。
