Paradoxical Pharmacological Effects of Deoxy-Tetrahydrocannabinol Analogs Lacking High CB₁ Receptor Affinity

Abstract

The present study investigated the role of peripheral cannabinoid (CB₂) receptors in producing hypomobility, antinociception and hypothermia in mice. Results revealed that the CB₂-selective antagonist, SR144528, did not block cannabimimetic effects of a potent Δ⁸-tetrahydrocannabinol (THC) analog in mice. While most of a series of CB₂-selective 1-deoxy-THC analogs were active in vivo only if they also had good affinity for CB₁ receptors, four of these analogs showed in vivo activity even though their affinities for CB₁ receptors were poor. Further, this activity was blocked by the CB₁ antagonist SR141716A, but not by SR144528. One of the deoxy analogs also stimulated [³⁵S]GTPγS binding, an effect that was blocked by SR141716A. These results provide further evidence that these cannabimimetic effects are not mediated through action at CB₂ receptors. In addition, some of these analogs may be very low efficacy agonists at CB₁ receptors that act as full agonists in vivo, but lack the ability to displace high affinity and high efficacy binding ligands in vitro.

Comparison of the discriminative stimulus and response rate effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats

“…Rimonabant’s decreased potency in males also has been noted with respect to reversal of cannabinoid-induced antinociceptive effects (Craft et al, 2012). As reported previously for male rodents (Järbe et al, 2006; Wiley et al, 2002), the CB 2 antagonist SR144528 failed to antagonize THC’s discriminative stimulus effects in female rats, and small leftward shifts in the THC dose-response curve were noted, raising the possibility that pharmacological elimination of THC’s CB 2 agonist properties may enhance the drug’s CB 1 receptor mediated effects. This result is consistent with the previously suggested hypothesis that involvement of CB 2 receptors may be greater in mediation of THC’s pharmacological effects in female (vs. male) rats (Craft et al, 2013a; Craft et al, 2012).…”

Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid CB1 receptor antagonist

“…While cannabinoid discrimination in mice is relatively novel (most previous research in this area was done in rats), it has been used successfully to distinguish cannabinoids from non-cannabinoids (McMahon et al, 2007; Vann et al, 2009). Further, in the present study, JWH-104, a Δ 8 -tetrahydrocannabinol analog from another series (Wiley et al, 2002), did not substitute for Δ 9 -tetrahydrocannabinol, suggesting that substitution was somewhat selective in that it did not occur across all cannabinoids within this class. Several other factors may have contributed to the disconnection between the agonist-like substitution for Δ 9 -tetrahydrocannabinol in a drug discrimination procedure and the absence of O-2050 effects in the triad of in vivo assays.…”

“…Finally, the degree to which interaction of O-2050 with cannabinoid CB 2 receptors may have modulated responses in the different procedures is unknown. Although a direct role of cannabinoid CB 2 receptors alone in mediation of effects in the triad and discriminative stimulus effects of cannabinoid agonists has been ruled out (Järbe et al, 2006; Wiley et al, 2002), possible effects of interactions among cannabinoid CB 1 and CB 2 receptor mechanisms in these behaviors have not been extensively explored.…”

Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: Steric and electronic effects of 4- and 8-halogenated naphthoyl substituents

“…Similar to the results observed here with JWH-415, JWH-104 has low CB 1 affinity (K i = 909 nM); yet, it produced cannabimimetic effects in the battery of mouse tests that were blocked by rimonabant. 35 Results of a [ 35 S]GTPγS binding assay showed that JWH-104 also functions as a low efficacy agonist at CB 1 receptors. Interestingly, JWH-104 did not substitute for THC in a drug discrimination procedure in mice (an animal model of marijuana-like intoxication), 36,37 suggesting that it does not produce the entire complement of cannabinoid effects seen with THC.…”