title: An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers.
abstract: Pharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer's disease, social disorders, cachexia, and obesity. This study focused on the design and synthesis of bivalent ligands to target melanocortin receptor homodimers. Lead ligands increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts. Unexpectedly, different bivalent ligands showed preferences for particular melanocortin receptor subtypes depending on the linker that connected the binding scaffolds, suggesting structural differences between the various dimer subtypes. Homobivalent compound 12 possessed a functional profile that was unique from its monovalent counterpart providing evidence of the discrete effects of bivalent ligands. Lead compound 7 significantly decreased feeding in mice after intracerebroventricular administration. To the best of our knowledge, this is the first report of a melanocortin bivalent ligand's in vivo physiological effects.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Lensing
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Katie T
authors.initials: KT
authors.lastname: Freeman
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Sathya M
authors.initials: SM
authors.lastname: Schnell
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Adank
authors.affiliation: College of Pharmacy, Nova Southeastern University , Fort Lauderdale, Florida 33328-2018, United States.|Department of Pharmacology and Physiology, Georgetown University , Washington, D.C. 20057, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Speth
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D060326:Chemistry Techniques, Synthetic; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004435:Eating / Q000187:drug effects; D005260:Female; D006801:Humans; D057967:Infusions, Intraventricular; D008024:Ligands; D008297:Male; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055503:Protein Multimerization; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; C574273:MC4R protein, mouse; C470053:Mc3r protein, mouse; D010455:Peptides; D044102:Receptor, Melanocortin, Type 1; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; C086971:melanocortin 5 receptor; D000242:Cyclic AMP