An investigation into the structural determinants of cannabinoid receptor ligand efficacy

Abstract

A number of side‐chain analogues of Δ8‐THC were tested in GTPγS binding assay in rat cerebellar membranes. O‐1125, a saturated side‐chain compound stimulated GTPγS binding with an Emax of 165.0%, and an EC50 of 17.4 nM. O‐1236, O‐1237 and O‐1238, three‐enyl derivatives containing a cis carbon‐carbon double bond in the side‐chain, stimulated GTPγS binding, acting as partial agonists with Emax values ranging from 51.3–87.5% and EC50 values between 4.4 and 29.7 nM. The stimulatory effects of O‐1125, O‐1236, O‐1237 and O‐1238 on GTPγS binding were antagonized by the CB1 receptor antagonist SR 141716A. The KB values obtained ranged from 0.11–0.21 mM, suggesting an action at CB1 receptors. Five‐ynyl derivatives (O‐584, O‐806, O‐823, O‐1176 and O‐1184), each containing a carbon‐carbon triple bond in the side‐chain, did not stimulate GTPγS binding and were tested as potential cannabinoid receptor antagonists. Each ‐ynyl compound antagonized the stimulatory effects of four cannabinoid receptor agonists on GTPγS binding. The KB values obtained, all found to be in the nanomolar range, did not differ between agonists or from cerebellar binding affinity. In conclusion, alterations of the side‐chain of the classical cannabinoid structure may exert a large influence on affinity and efficacy at the CB1 receptor. Furthermore, this study confirms the ability of the GTPγS binding assay to assess discrete differences in ligand efficacies which potentially may not be observed using alternative functional assays, thus providing a unique tool for the assessment of the molecular mechanisms underlying ligand efficacies. British Journal of Pharmacology (1999) 126, 1575–1584; doi:

Some effects of CB1 antagonists with inverse agonist and neutral biochemical properties

“…This is a potentially attractive concept; yet, there currently is very little information to either support or challenge this proposition. Previous studies of allosteric regulation of the CB1 receptor showed that allosteric regulators could be used to manipulate the affinity of CB1 agonists but not of SR141716A, suggesting that it functioned as a neutral antagonist in such binding assays [24]. It also has been reported that the magnitude of inverse agonist action that is produced by antagonist concentrations of SR141716A on forskolin-stimulated accumulation of cAMP is moderate, raising the possibility that SR141716A may serve as a partial inverse agonist in this assay.…”

CB1 Cannabinoid Receptor Ligands

“…Later binding experiments with rat cerebellar membranes using [ 35 S]-GTPγ S found this compound to behave as a low-efficacy agonist at CB1 receptors [76,77].…”

Dissecting AI-2-mediated quorum sensing through C5-analogue synthesis and biochemical analysis

“…10 Although non-fluoro alkyl halides have the potential to undergo nucleophilic displacement and are widely considered to be genotoxic fragments, drugs containing alkyl chloride motifs are generally stable in vivo and are relatively common. 11 There are also examples of alkyl bromides being used in medicinal chemistry with apparent stability (cannabinoid receptor agonists O-806 and O-1236 12 ), although electrophilic reactivity is anticipated. However, alkyl iodides are scarcely reported in this context due to their instability; in our context, C5-I-DPD would almost certainly act as an alkylating agent or simply hydrolyse to form DPD.…”