title: One for the Price of Two…Are Bivalent Ligands Targeting Cannabinoid Receptor Dimers Capable of Simultaneously Binding to both Receptors?
abstract: Bivalent ligands bridging two G-protein-coupled receptors (GPCRs) provide valuable pharmacological tools to target oligomers. The success of therapeutically targeting the cannabinoid CB1 receptor has been limited, in part due to its widespread neuronal distribution. Therefore, CB1 ligands targeting oligomers that exhibit restricted distribution or altered pharmacology are highly desirable, and several bivalent ligands containing a CB1 pharmacophore have been reported. Bivalent ligand action presumes that the ligand simultaneously binds to both receptors within the dimeric complex. However, based on the current understanding of CB1 ligand binding, existing bivalent ligands are too short to bind both receptors simultaneously. However, ligands with longer linkers may not be the solution, because evidence suggests that ligands enter CB1 through the lipid bilayer and, thus, linkers are unlikely to exit the receptor through its external face. Thus, the entire premise of designing bivalent ligands targeting CB1 must be revisited.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. Electronic address: m.glass@auckland.ac.nz.
authors.forename: Michelle
authors.initials: M
authors.lastname: Glass
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Karan
authors.initials: K
authors.lastname: Govindpani
authors.affiliation: School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Furkert
authors.affiliation: Center for Drug Design, University of North Carolina Greensboro, Greensboro, NC 27402, USA.
authors.forename: Dow P
authors.initials: DP
authors.lastname: Hurst
authors.affiliation: Center for Drug Design, University of North Carolina Greensboro, Greensboro, NC 27402, USA.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand; Auckland Cancer Society Research Centre and Maurice Wilkens Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
mesh_terms: D063386:Cannabinoid Receptor Agonists / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D055503:Protein Multimerization; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D063386:Cannabinoid Receptor Agonists; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid
keywords: G-protein-coupled receptors; dual-acting ligands; heteromer; oligomers