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Signalling trafficking of allosteric modulator, ORG27569 at the cannabinoid CB1 receptor ORG27569, an allosteric modulator of the cannabinoid CB1 receptor (Price et al, 2005), increases the binding affinity of agonists for CB1 receptors but reduces the signalling efficacy of these receptors. It has been suggested that allosteric modulators can have differential effects on various signalling pathways (Zhang et al, 2005). The aim of the present study was to investigate how the allosteric modulator of CB1, ORG27569, affects different signalling pathways that are linked to the CB1 receptor. The effect of ORG27569 on agonist-induced CB1 receptor signalling was investigated using [35S]GTPγS binding, cyclic AMP, beta arrestin and pERK assays. ORG27569 displayed different effects on CP55940 signalling. Table 1 summarises the effect of 100nM or 1µM ORG27569 on CP55940 signalling in all assays investigated. Table 1: Emax values with 95% confidence limits and pEC50 values for the effect of ORG27569 on the CB1 receptor agonist CP55940 in each assay type.
100nM ORG27569 completely abolished the effect of CP55940 in both the beta arrestin assay and cyclic AMP assay compared to the [35S]GTPγS binding assay in which 100nM ORG27569 attenuated the effect of CP55940 and the pERK assay in which 1µM ORG2759 had no significant effect on CP55940 functional efficacy. These data provide evidence that allosteric modulators binding to the cannabinoid CB1 receptor can preferentially impact signalling through some pathways and not others. This indicates that allosteric modulators could be used to selectively alter a desired or undesired response to receptor activation without affecting others.
Price, M.R et al. (2005) Mol Pharmacol 68, 1484-1495 Zhang, Y et al. (2005) J. Pharmacol Exp Ther 315 (3), 1212-1219 Funded by NIH (DA-03672). values with 95% confidence limits and pEC values for the effect of ORG27569 on the CB receptor agonist CP55940 in each assay type.
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