CB₁-independent mechanisms of Δ⁹-THCV, AM251 and SR141716 (rimonabant).
The potential beneficial therapeutic effects of cannabinoid CB₁ receptor antagonists or partial agonists have driven drug discovery and development efforts and have led to clinical candidates. It is generally assumed that these compounds are CB₁ selective and produce their effects exclusively via CB₁ receptors. A literature search was conducted of preclinical publications containing information about non-CB₁ receptor pharmacology of these agents. The information was summarized and evaluated from the perspective of contribution to a fuller understanding of this aspect of these compounds. A number of recent studies have revealed that these compounds have CB₁-independent pharmacological actions. We highlight the evidence regarding effects produced in cells lacking CB₁ receptors, effects on neuronal membranes from CB₁ receptor-deficient mutant KO knockout mice and affinity for μ-opioid receptors. CB₁ selective antagonists and partial agonists have been studied for their anorexigenic and other potential therapeutic uses. An awareness of CB₁-independent mechanism(s) of these agents might contribute to a better understanding of the pharmacologic and toxicologic profiles of these agents.