title: Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR5).
abstract: Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that a MOR-CCR5 heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED50 = 0.0146 pmol/mouse) that was 2000× greater than morphine. Moreover, MCC22 was ~3500× more potent than a mixture of mu agonist and CCR5 antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR5 heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR5 heteromer as a novel target for the treatment of chronic pain.
authors.affiliation: Department of Medicinal Chemistry, and ‡Center for Drug Design, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Eyup
authors.initials: E
authors.lastname: Akgün
authors.affiliation: Department of Medicinal Chemistry, and ‡Center for Drug Design, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Muhammad I
authors.initials: MI
authors.lastname: Javed
authors.affiliation: Department of Medicinal Chemistry, and ‡Center for Drug Design, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Lunzer
authors.affiliation: Department of Medicinal Chemistry, and ‡Center for Drug Design, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Powers
authors.affiliation: Department of Medicinal Chemistry, and ‡Center for Drug Design, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Yuk Y
authors.initials: YY
authors.lastname: Sham
authors.affiliation: Department of Medicinal Chemistry, and ‡Center for Drug Design, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Medicinal Chemistry, and ‡Center for Drug Design, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Portoghese
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D065100:CCR5 Receptor Antagonists / Q000737:chemistry* / Q000627:therapeutic use*; D002908:Chronic Disease; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009437:Neuralgia / Q000188:drug therapy* / Q000276:immunology; D019713:Receptors, CCR5 / Q000276:immunology*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000276:immunology
chemical_list: D000700:Analgesics; D065100:CCR5 Receptor Antagonists; D019713:Receptors, CCR5; D017450:Receptors, Opioid, mu