title: (3-Aminocyclopentyl)methylphosphinic acids: novel GABA(C) receptor antagonists.
abstract: Our understanding of the role GABA(C) 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 GABA(C) receptor showing little activity at GABA(A) or GABA(B) receptors. (+/-)-cis-3-ACPMPA has similar potency to (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at human recombinant rho1 (K(B)=1.0+/-0.2microM) and rat rho3 (K(B)=5.4+/-0.8microM) but is 15 times more potent than TPMPA on human recombinant rho2 (K(B)=1.0+/-0.3microM) GABA(C) receptors expressed in Xenopus oocytes. (+/-)-cis- and (+/-)-trans-3-ACPMPA are novel lead compounds for developing into more potent and selective GABA(C) receptor antagonists with increased lipophilicity for in vivo studies.
authors.affiliation: Faculty of Pharmacy, Pharmacy Building A15, The University of Sydney, NSW 2006, Australia. maryc@pharm.usyd.edu.au
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.forename: Jane R
authors.initials: JR
authors.lastname: Hanrahan
authors.forename: Rohan J
authors.initials: RJ
authors.lastname: Kumar
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Mewett
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Morriss
authors.forename: Soraya
authors.initials: S
authors.lastname: Wooller
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Johnston
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D009865:Oocytes; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D018079:Receptors, GABA / Q000502:physiology; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; C087200:GABA-C receptor; D009943:Organophosphorus Compounds; D018079:Receptors, GABA; C068457:3-aminopropyl(methyl)phosphinic acid; D005680:gamma-Aminobutyric Acid