BivalentLigands That Target μ Opioid (MOP)and Cannabinoid1 (CB1) Receptors Are Potent AnalgesicsDevoid of Tolerance.

Given that μ opioid (MOP) andcanabinoid (CB1)receptors are colocalized in various regions of the central nervoussystem and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenousMOP-CB1in nociception and other pharmacologic effectshas been raised. As a first step in investigating this possibility,we have synthesized a series of bivalent ligands 1–5that contain both μ agonist and CB1antagonistpharmacophores for use as tools to study the functional interactionbetween MOP and CB1receptors in vivo. Immunofluorescentstudies on HEK293 cells coexpressing both receptors suggested 5(20-atom spacer) to be the only member of the series thatbridges the protomers of the heteromer. Antinociceptive testing inmice revealed 5to be the most potent member of the series.As neither a mixture of monovalent ligands 9+ 10nor bivalents 2–5producedtolerance in mice, MOR-CB1apparently is not an importanttarget for reducing tolerance. [ABSTRACT FROM AUTHOR]