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Allosteric enhancement of the cannabinoid CB1 receptor There is evidence for an allosteric binding site on the cannabinoid CB1 receptor (Price et al., 2005). The aim of this study was to extend preliminary findings that have been obtained with a putative allosteric enhancer of the CB1 receptor, F0870064 (Adam et al., 2007). Radioligand binding assays were used to investigate the effects of F0870064 on agonist dissociation rate and binding affinity. Functional effects on agonist signalling efficacy were investigated using [35S]GTPγS binding assays in mouse brain membranes. Variability is expressed as 95% confidence limits (CL). F0870064 (1 and 10 μM) significantly slowed the dissociation rate of [3H]CP55940 from mouse brain membranes. It also caused a significant increase in the specific binding of [3H]CP55940 in the equilibrium binding assay of 38.1% (95% CL = 16.6 - 59.6%). In the [35S]GTPγS binding assay F0870064 (1μM) significantly increased the efficacy of the endocannabinoid, anandamide, with Emax values of 59.5% (CL = 51.4-67.6%) and 110.2% (CL = 99-121%) for vehicle control and F0870064, respectively. F0870064 (1μM) also significantly increased the efficacy of the synthetic cannabinoid, WIN55212-2, and phytocannabinoid, Δ9-THC. Emax values in the presence of vehicle or F0870064 were 90% (CL = 81-99%) and 126% (CL = 115-136%), respectively for WIN55212-2, and 10% (CL = 2-17%) and 61% (CL = 43-78%), respectively for Δ9-THC. F08700764 (1μM) did not significantly increase the efficacy of the synthetic cannabinoid CP55940. Here we provide further evidence for allosteric enhancement of cannabinoid CB1 receptor agonist affinity and efficacy. The availability of an allosteric enhancer of this receptor may provide a means of activating CB1 receptors in the clinic with an improved benefit to risk ratio.
Price MR et al. (2005) Mol Pharmacol 68: 1484-1495.∼
Funded by NIH (DA-09789).
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