Bivalent Ligands That Target μ Opioid (MOP) and Cannabinoid1 (CB1) Receptors Are Potent Analgesics Devoid of Tolerance

• Published in: Journal of medicinal chemistry 2013-07, Vol.56 (13), p.5505-5513
• Main Authors: Le Naour, Morgan, Akgün, Eyup, Yekkirala, Ajay, Lunzer, Mary M, Powers, Mike D, Kalyuzhny, Alexander E, Portoghese, Philip S
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - chemical synthesis; Analgesics, Opioid - chemistry; Analgesics, Opioid - pharmacology; Animals; Cell Membrane - drug effects; Cell Membrane - metabolism; Drug Design; Drug Tolerance; Endocytosis - drug effects; Fluorescent Antibody Technique; HEK293 Cells; Humans; Injections, Intraventricular; Injections, Spinal; Ligands; Male; Mice, Inbred ICR; Models, Chemical; Molecular Structure; Pain - physiopathology; Pain - prevention & control; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4005219

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.