title: The cannabinoid CB1 receptor antagonists rimonabant (SR141716) and AM251 directly potentiate GABA(A) receptors.
abstract: OBJECTIVE
  Rimonabant (SR141716) and the structurally related AM251 are widely used in pharmacological experiments as selective cannabinoid receptor CB(1) antagonists / inverse agonists. Concentrations of 0.5-10 µM are usually applied in in vitro experiments. We intended to show that these drugs did not act at GABA(A) receptors but found a significant positive allosteric modulation instead.
  
  
  METHODS
  Recombinant GABA(A) receptors were expressed in Xenopus oocytes. Receptors were exposed to AM251 or rimonabant in the absence and presence of GABA. Standard electrophysiological techniques were used to monitor the elicited ionic currents.
  
  
  RESULTS
  AM251 dose-dependently potentiated responses to 0.5 µM GABA at the recombinant α(1) β(2) γ(2) GABA(A) receptor with an EC(50) below 1 µM and a maximal potentiation of about eightfold. The Hill coefficient indicated that more than one binding site for AM251 was located in this receptor. Rimonabant had a lower affinity, but a fourfold higher efficacy. AM251 potentiated also currents mediated by α(1) β(2) , α(x) β(2) γ(2) (x = 2,3,5,6), α(1) β(3) γ(2) and α(4) β(2) δ GABA(A) receptors, but not those mediated by α(1) β(1) γ(2) . Interestingly, the CB(1) receptor antagonists LY320135 and O-2050 did not significantly affect α(1) β(2) γ(2) GABA(A) receptor-mediated currents at concentrations of 1 µM.
  
  
  CONCLUSIONS
  This study identified rimonabant and AM251 as positive allosteric modulators of GABA(A) receptors. Thus, potential GABAergic effects of commonly used concentrations of these compounds should be considered in in vitro experiments, especially at extrasynaptic sites where GABA concentrations are low.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstr, Bern, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Baur
authors.forename: J
authors.initials: J
authors.lastname: Gertsch
authors.forename: E
authors.initials: E
authors.lastname: Sigel
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D011963:Receptors, GABA-A / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000077285:Rimonabant; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C508712:(6aR,10aR)-3-(1-methansulfonylamino-4-hexyn-6-yl)6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo(b,d)pyran; D001572:Benzofurans; D010880:Piperidines; D011714:Pyrans; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C103505:AM 251; D005680:gamma-Aminobutyric Acid; D013759:Dronabinol; C110158:LY 320135; D000077285:Rimonabant