Faculty Articles

Title

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

Publication Title

Journal of Medicinal Chemistry

Volume

59

Issue

7

Publication Date / Copyright Date

4-14-2016

First Page

3112

Last Page

3128

Publisher

American Chemical Society

DOI Number

10.1021/acs.jmedchem.5b01894

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.

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Keywords

Animals, Binding, Competitive, Chemistry Techniques, Synthetic, Cyclic AMP, Drug Design, Drug Evaluation, Preclinical, Eating, Female, Humans, Infusions, Intraventricular, Ligands, Male, Mice, Inbred C57BL, Peptides, Protein Multimerization, Receptor, Melanocortin, Type 1, Receptor, Melanocortin, Type 3, Receptor, Melanocortin, Type 4, Receptors, Melanocortin, Structure-Activity Relationship

Peer Reviewed

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