Allosteric modulation of the cannabinoid CB1 receptor

M R Price, G L Baillie, Adele Thomas, Lesley Ann Stevenson, M Easson, R Goodwin, A McLean, L McIntosh, G Goodwin, G Walker, P Westwood, J Marrs, F Thomson, P Cowley, A Christopoulos, Roger Guy Pertwee, Ruth Alexandra Ross

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366 Citations (Scopus)


We investigated the pharmacology of three novel compounds, Org 27569 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)-ethyl]-amide), Org 27759 (3-ethyl-5-fluoro-1H-indole-2-carboxylic acid [2-94-dimethylamino-phenyl)ethyl]-amide), and Org 29647 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide, 2-enedioic acid salt), at the cannabinoid CB1 receptor. In equilibrium binding assays, the Org compounds significantly increased the binding of the CB1 receptor agonist [H-3]CP 55,940 [(1R,3R,4R)3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol], indicative of a positively cooperative allosteric effect. The same compounds caused a significant, but incomplete, decrease in the specific binding of the CB1 receptor inverse agonist [H-3]SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride], indicative of a limited negative binding cooperativity. Analysis of the data according to an allosteric ternary complex model revealed that the estimated affinity of each Org compound was not significantly different when the radioligand was [H-3]CP 55,940 or [H-3]SR 141716A. However, the estimated cooperatively factor for the interaction between modulator and radioligand was greater than 1 when determined against [H-3]CP 55,940 and less than 1 when determined against [H-3]SR 141716A. [H-3]CP 55,940 dissociation kinetic studies also validated the allosteric nature of the Org compounds, because they all significantly decreased radioligand dissociation. These data suggest that the Org compounds bind allosterically to the CB1 receptor and elicit a conformational change that increases agonist affinity for the orthosteric binding site. In contrast to the binding assays, however, the Org compounds behaved as insurmountable antagonists of receptor function; in the reporter gene assay, the guanosine 5'-O-(3-[S-35]thio)triphosphate binding assay and the mouse vas deferens assay they elicited a significant reduction in the E-max value for CB1 receptor agonists. The data presented clearly demonstrate, for the first time, that the cannabinoid CB1 receptor contains an allosteric binding site that can be recognized by synthetic small molecule ligands.

Original languageEnglish
Pages (from-to)1484-1495
Number of pages12
JournalMolecular Pharmacology
Issue number5
Publication statusPublished - Nov 2005


  • protein-coupled receptors
  • endocannabinoid system
  • international union
  • binding
  • pharmacology
  • ligands
  • pain
  • classification
  • acetylcholine
  • antagonist


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