Stratification of Cannabinoid 1 Receptor (CB₁R) Agonist Efficacy: Manipulation of CB₁R Density through Use of Transgenic Mice Reveals Congruence between In Vivo and In Vitro Assays

Abstract

Synthetic cannabinoids (SCs) are an emerging class of abused drugs that differ from each other and the phytocannabinoid ∆-tetrahydrocannabinol (THC) in their safety and cannabinoid-1 receptor (CBR) pharmacology. As efficacy represents a critical parameter to understanding drug action, the present study investigated this metric by assessing in vivo and in vitro actions of THC, two well-characterized SCs (WIN55,212-2 and CP55,940), and three abused SCs (JWH-073, CP47,497, and A-834,735-D) in CB (+/+), (+/-), and (-/-) mice. All drugs produced maximal cannabimimetic in vivo effects (catalepsy, hypothermia, antinociception) in CB (+/+) mice, but these actions were essentially eliminated in CB (-/-) mice, indicating a CBR mechanism of action. CBR efficacy was inferred by comparing potencies between CB (+/+) and (+/-) mice [+/+ ED /+/- ED], the latter of which has a 50% reduction of CBRs (i.e., decreased receptor reserve). Notably, CB (+/-) mice displayed profound rightward and downward shifts in the antinociception and hypothermia dose-response curves of low-efficacy compared with high-efficacy cannabinoids. In vitro efficacy, quantified using agonist-stimulated [S]GTPγS binding in spinal cord tissue, significantly correlated with the relative efficacies of antinociception (r = 0.87) and hypothermia (r = 0.94) in CB (+/-) mice relative to CB (+/+) mice. Conversely, drug potencies for cataleptic effects did not differ between these genotypes and did not correlate with the in vitro efficacy measure. These results suggest that evaluation of antinociception and hypothermia in CB transgenic mice offers a useful in vivo approach to determine CBR selectivity and efficacy of emerging SCs, which shows strong congruence with in vitro efficacy.

Medications for substance use disorders (SUD): emerging approaches

“…The CB1-r partial agonist Δ9-tetra-hydrocannabinol (Δ9-THC) is the main active product from Cannabis sativa [49]. Preparations containing Δ9-THC are the focus of much non-medical usage, and cannabis use disorders are relatively frequent [1,50].…”

“…CB1-r, which are also GPCRs, are found in diverse brain areas that mediate motivation, reward and cognition [51,52]. Several synthetic CB1-r agonists have also become the focus of abuse in recent years, and these have higher pharmacodynamic efficacy at CB1-r, compared to Δ9-THC [49]. Another product from the C. sativa plant is cannabidiol, which is not considered to have abuse potential per se [52].…”

“…The potential pharmacotherapeutic use of cannabinoid formulations has been studied in specific SUD (including aspects of opioid use disorder), but their effectiveness is not broadly supported at this time [79,146,147]. CB1-r receptor systems can also be targeted by synthetic small molecules, and synthetic CB1-r full agonists are also abused [49,148]. Synthetic molecules with appropriate PD/PK (for example, CB1-r antagonists or partial agonists with prolonged durations of action) may be considered as pharmacotherapeutic strategies in specific SUD [49].…”

“…CB1-r receptor systems can also be targeted by synthetic small molecules, and synthetic CB1-r full agonists are also abused [49,148]. Synthetic molecules with appropriate PD/PK (for example, CB1-r antagonists or partial agonists with prolonged durations of action) may be considered as pharmacotherapeutic strategies in specific SUD [49]. For example, a CB1-r antagonist or inverse agonist, rimonabant, showed some promising effects in smoking cessation in humans, as described in a recent review [149].…”

The Contribution of Studies with Canabidiol and Synthetic Analogues in the Design of New Drug Candidates for Neuropsychiatric Disorders and Neurodegenerative Diseases

“…Seu mecanismo de ação está baseado em seu efeito agonista de CB1 altamente eficaz, ocasionando efeitos narcótico, alucinógeno, depressor e dependência. 17 Por outro lado, alguns análogos sintéticos de canabinoides naturais e de seus metabólitos, a exemplo de HU-308 (8); O-1602 (9) e HU-308 (10, Figura 3), atuam como antagonistas de receptores canabinoides e moduladores do sistema canabinoide endógeno, e vêm sendo estudados como novos candidatos promissores para pesquisas clínicas e uso terapêutico.…”