Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance

Abstract

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.

Figure 2

Single cell high-magnification images of double-labeling immunofluorescence for co-expressed MOP and CB₁ receptors on HEK-293 cells. The identical cells are shown labeled for MOP (red fluorescence) and CB₁ (green fluorescence) receptors. Arrows depict profiles double-labeled for MOP and CB1.

Figure 2

Single cell high-magnification images of double-labeling immunofluorescence for co-expressed MOP and CB₁ receptors on HEK-293 cells. The identical cells are shown labeled for MOP (red fluorescence) and CB₁ (green fluorescence) receptors. Arrows depict profiles double-labeled for MOP and CB1.

Scheme 1

Intermediates for synthesis of bivalent ligands 1-5 and monovalent ligands 9 and 10

Scheme 2

Synthesis of target compounds (1-5, 10)