title: Heteromer Induction: An Approach to Unique Pharmacology?
abstract: It is proposed that two types of opioid receptor heteromers exist: a) those that are constitutive and b) those that are induced by bivalent ligands. Mu opioid agonists interact with constitutive MOR-DOR heteromer to mediate tolerance and dependence. Bivalent ligand, MDAN21, is devoid of these adverse effects by virtue of its DOR antagonist pharmacophore. We propose that bivalent ligands MMG22 and MCC22 induce colocalized receptors to form heteromers (MOR-mGluR5 and MOR-CCR5, respectively) that do not occur naturally, thereby promoting unique pharmacology. Heteromer induction with bivalent ligands offers a general approach to unique pharmacology that complements traditional SAR.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Portoghese
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Eyup
authors.initials: E
authors.lastname: Akgün
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Lunzer
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000737:chemistry; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D064529:Receptor, Metabotropic Glutamate 5; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
keywords: DOR; MOR; heterodimer; opiod receptor