Novel gamma-aminobutyric acid rho1 receptor antagonists; synthesis, pharmacological activity and structure-activity relationships.
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.
Faculty of Pharmacy, University of Sydney, NSW, Australia.
Rohan J
RJ
Kumar
Mary
M
Chebib
David E
DE
Hibbs
Hye-Lim
HL
Kim
Graham A R
GA
Johnston
Noeris K
NK
Salam
Jane R
JR
Hanrahan
D000818:Animals; D005260:Female; D018756:GABA Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D018756:GABA Antagonists; D008024:Ligands