Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB ₁) receptors are potent analgesics devoid of tolerance

Given that μ opioid (MOP) and canabinoid (CB₁) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB₁) in cultured cells, the possibility of functional, endogenous MOP-CB₁ in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both μ agonist and CB₁ antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB₁ receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB₁ apparently is not an important target for reducing tolerance.