Apparent CB₁ Receptor Rimonabant Affinity Estimates: Combination with THC and Synthetic Cannabinoids in the Mouse In Vivo Triad Model

Abstract

Synthetic cannabinoids (SCs) represent an emerging class of abused drugs associated with psychiatric complications and other substantial health risks. These ligands are largely sold over the internet for human consumption, presumably because of their high cannabinoid 1 receptor (CBR) affinity and their potency in eliciting pharmacological effects similar to Δ-tetrahydrocannabinol (THC), as well as circumventing laws illegalizing this plant. Factors potentially contributing to the increased prevalence of SC abuse and related hospitalizations, such as increased CBR efficacy and non-CBR targets, highlight the need for quantitative pharmacological analyses to determine receptor mediation of the pharmacological effects of cannabinoids. Accordingly, the present study used pA and pK analyses for quantitative determination of CBR mediation in which we utilized the CBR-selective inverse agonist/antagonist rimonabant to elicit rightward shifts in the dose-response curves of five SCs (i.e., A-834,735D; WIN55,212-2; CP55,950; JWH-073; and CP47,497) and THC in producing common cannabimimetic effects (i.e., catalepsy, antinociception, and hypothermia). The results revealed overall similarity of pA and pK values for these compounds and suggest that CBRs, and not other pharmacological targets, largely mediated the central pharmacological effects of SCs. More generally, affinity estimation offers a powerful pharmacological approach to assess potential receptor heterogeneity subserving in vivo pharmacological effects of SCs.

Finding order in chemical chaos - Continuing characterization of synthetic cannabinoid receptor agonists

“…The CB 1 receptor affinity of these synthetic cannabinoids correlated with their potency in the drug discrimination assay; however, this was not observed with CB 2 receptor affinity. These findings are consistent with previous observations that the discriminative stimulus effects of these synthetic cannabinoids are CB 1 receptor dependent, as verified by the CB 1 R-selective inverse agonist/antagonist rimonabant eliciting rightward shifts in the dose-response curve, and pA 2 and pK B analyses for quantitative confirmation of CB 1 R mediation (Grim et al, 2016; Grim et al, 2017; Hruba & McMahon, 2017).…”

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB1/CB2 versus GPR55 receptors

“…The first important finding in the present experiment is that CB 1 receptors are critically involved in the three cannabinoid‐induced tetrad effects, that is, those produced by Δ 9 ‐THC, WIN55212‐2 and XLR11. This is fully consistent with previous reports that pharmacological blockade or genetic deletion of CB 1 receptors attenuated or abolished Δ 9 ‐THC‐ or WIN55212‐2‐induced tetrad effects (Abalo et al, ; Compton, Aceto, Lowe, & Martin, ; Fox et al, ; Grim et al, ; Ledent et al, ; Varvel et al, ). It is well documented that CB 1 receptors are broadly expressed in both the CNS and peripheral tissues (Howlett & Abood, ), but it is to be determined whether brain or peripheral CB 1 receptors underlie cannabinoid‐induced tetrad effects.…”

In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa

“…Moreover, the partial agonist effects displayed by these ligands suggests they may be functionally antagonistic in the presence of higher agonist concentrations and in vivo. This functional antagonism has been previously demonstrated for ∆ 9 -THC itself when administered alongside full and potent CB1R agonists 10,[53][54][55][56] . A growing body of literature also supports the notion that phytocannabinoids such as ∆ 9 -THCa, CBD, and others may be able to occupy both orthosteric and allosteric sites with varying affinity, further complicating our understanding of the cannabinoid receptors 10,15,29 .…”