Novel γ-Aminobutyric Acid ρ₁ Receptor Antagonists; Synthesis, Pharmacological Activity and Structure−Activity Relationships

γ-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 ρ₁ 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 ρ₁ receptors (36, K_B = 0.78 μM) and selectivity greater than 100 times (41, K_B = 4.97 μM) were obtained. The data obtained was analyzed along with the known set of GABA_C ρ₁ receptor−ligands, leading to the development of a pharmacophore model for this receptor, which can be used for in silico screening.