Document Type

Article

Publication Date

3-12-2020

Publication Title

Journal of Medicinal Chemistry

ISSN

0022-2623

Volume

63

Issue/No.

5

First Page

2194

Last Page

2208

Abstract

While the melanocortin receptors (MCRs) are known to be involved in numerous biological pathways, the potential roles of the MC5R have not been clearly elucidated in humans. Agouti-related protein (AgRP), an MC3R/MC4R antagonist and MC4R inverse agonist, contains an exposed β-hairpin loop composed of six residues (Arg-Phe-Phe-Asn-Ala-Phe) that is imperative for binding and function. Within this active loop of AgRP, four human missense polymorphisms were deposited into the NIH Variation Viewer database. These polymorphisms, Arg111Cys, Arg111His, Phe112Tyr, and Ala115Val (AgRP full-length numbering), were incorporated into the peptide macrocycles c[Pro-Arg-Phe-Phe-Xaa-Ala-Phe-dPro], where Xaa was Dap or Asn, to explore the functional effects of these naturally occurring substitutions in a simplified AgRP scaffold. All peptides lowered potency at least 10-fold in a cAMP accumulation assay compared to the parent sequences at the MC4Rs. Compounds MDE 6-82-3c, ZMK 2-82, MDE 6-82-1c, ZMK 2-85, and ZMK 2-112 are also the first AgRP-based chemotypes that antagonize the MC5R.

ORCID ID

0000-0002-6434-2149

DOI

10.1021/acs.jmedchem.9b00860

Download
Peer Reviewed

Find in your library

Share

COinS