Faculty Articles

Publication Title

Journal of Medicinal Chemistry

Publisher

American Chemical Society

ISSN

0022-2623

Publication Date

4-14-2016

Keywords

Melanotropin, peptide, GPCR dimers, homobivalent, homodimer, obesity, feeding

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.

DOI

10.1021/acs.jmedchem.5b01894

Volume

59

Issue

7

First Page

3112

Last Page

3128

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Rights

© 2016 American Chemical Society

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