Sub-nanomolar hMC1R agonists by end-capping of the melanocortin tetrapeptide His-D-Phe-Arg-Trp-NH(2)

L N Koikov; F H Ebetino; M G Solinsky; D Cross-Doersen; J J Knittel

doi:10.1016/s0960-894x(03)00552-3

Sub-nanomolar hMC1R agonists by end-capping of the melanocortin tetrapeptide His-D-Phe-Arg-Trp-NH(2)

Bioorg Med Chem Lett. 2003 Aug 18;13(16):2647-50. doi: 10.1016/s0960-894x(03)00552-3.

Authors

L N Koikov¹, F H Ebetino, M G Solinsky, D Cross-Doersen, J J Knittel

Affiliation

¹ College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA. lkoikov@hotmail.com

PMID: 12873485
DOI: 10.1016/s0960-894x(03)00552-3

Abstract

Twenty three derivatives of the core fragment His(6)-D-Phe(7)-Arg(8)-Trp(9)-NH(2) end-capped with carboxylic and sulfonic acids were synthesized and evaluated at human melanocortin receptors (hMC1, hMC3, and hMC4Rs). The SAR within this series allowed us to map the hMCRs near the His(6) binding site and design a superpotent MC1R agonist, LK-184, Ph(CH(2))(3)CO-His-D-Phe-Arg-Trp-NH(2) (19) with EC(50) 0.01 nM (5 nM at MC3 and MC4Rs).

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Carboxylic Acids / chemistry
Cell Line
Histidine / chemistry
Humans
Models, Chemical
Oligopeptides / chemical synthesis*
Oligopeptides / chemistry*
Oligopeptides / metabolism
Oligopeptides / pharmacology
Peptide Fragments / chemistry
Protein Binding
Receptor, Melanocortin, Type 1 / agonists*
Receptor, Melanocortin, Type 1 / chemistry
Receptor, Melanocortin, Type 1 / metabolism
Structure-Activity Relationship
Sulfonic Acids / chemistry
alpha-MSH / chemistry

Substances

Carboxylic Acids
Oligopeptides
Peptide Fragments
Ph(CH(2))(3)CO-His-D-Phe-Arg-Trp-NH(2)
Receptor, Melanocortin, Type 1
Sulfonic Acids
Histidine
alpha-MSH