(3-Aminocyclopentyl)methylphosphinic acids: Novel GABAC receptor antagonists

Our understanding of the role GABAC receptors play in the central nervous system is limited due to a lack of specific ligands. Here we describe the pharmacological effects of (±)-cis-3- and (±)-trans-3-(aminocyclopentyl)methylphosphinic acids ((±)-cis- and (±)-trans-3-ACPMPA) as novel ligands for the GABAC receptor showing little activity at GABAA or GABAB receptors. (±)-cis-3-ACPMPA has similar potency to (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at human recombinant ρ1 (KB = 1.0 ± 0.2 μM) and rat ρ3 (KB = 5.4 ± 0.8 μM) but is 15 times more potent than TPMPA on human recombinant ρ2 (KB = 1.0 ± 0.3 μM) GABAC receptors expressed in Xenopus oocytes. (±)-cis- and (±)-trans-3-ACPMPA are novel lead compounds for developing into more potent and selective GABAC receptor antagonists with increased lipophilicity for in vivo studies.