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

Morgan Le Naour, Eyup Akgun, Ajay Yekkirala, Mary M. Lunzer, Mike D. Powers, Alexander E. Kalyuzhny, Philip S Portoghese

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)5505-5513
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number13
DOIs
StatePublished - Jul 11 2013

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Cannabinoid Receptor CB1
Opioid Analgesics
Analgesics
Ligands
Nociception
HEK293 Cells
Protein Subunits
Cultured Cells
Central Nervous System

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Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB 1) receptors are potent analgesics devoid of tolerance. / Le Naour, Morgan; Akgun, Eyup; Yekkirala, Ajay; Lunzer, Mary M.; Powers, Mike D.; Kalyuzhny, Alexander E.; Portoghese, Philip S.

In: Journal of Medicinal Chemistry, Vol. 56, No. 13, 11.07.2013, p. 5505-5513.

Research output: Contribution to journalArticle

Le Naour, Morgan ; Akgun, Eyup ; Yekkirala, Ajay ; Lunzer, Mary M. ; Powers, Mike D. ; Kalyuzhny, Alexander E. ; Portoghese, Philip S. / Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB 1) receptors are potent analgesics devoid of tolerance. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 13. pp. 5505-5513.
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AU - Powers, Mike D.

AU - Kalyuzhny, Alexander E.

AU - Portoghese, Philip S

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