Discovery of 1-amino-4-phenylcyclohexane-1-carboxylic acid and its influence on agonist selectivity between human melanocortin-4 and -1 receptors in linear pentapeptides

Xin-Jie Chu; David Bartkovitz; Waleed Danho; Joseph Swistok; Adrian Wai-Hing Cheung; Grazyna Kurylko; Karen Rowan; Mitch Yeon; Lucia Franco; Lida Qi; Li Chen; Keith Yagaloff

doi:10.1016/j.bmcl.2005.08.012

Discovery of 1-amino-4-phenylcyclohexane-1-carboxylic acid and its influence on agonist selectivity between human melanocortin-4 and -1 receptors in linear pentapeptides

Bioorg Med Chem Lett. 2005 Nov 15;15(22):4910-4. doi: 10.1016/j.bmcl.2005.08.012.

Authors

Xin-Jie Chu¹, David Bartkovitz, Waleed Danho, Joseph Swistok, Adrian Wai-Hing Cheung, Grazyna Kurylko, Karen Rowan, Mitch Yeon, Lucia Franco, Lida Qi, Li Chen, Keith Yagaloff

Affiliation

¹ Roche Research Center, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. xin-jie.chu@roche.com

PMID: 16169218
DOI: 10.1016/j.bmcl.2005.08.012

Abstract

Linear pentapeptides (Penta-cis-Apc-DPhe-Arg-Trp-Gly-NH2) containing 1-amino-4-phenylcyclohexane-1-carboxylic acid (cis-Apc) and substituted Apc are potent hMC4R agonists and they are inactive or weakly active in hMC1R, hMC3R, and hMC5R agonist assays. This study, together with our earlier report on 5-BrAtc, demonstrated the importance of replacing His6 with phenyl-containing rigid templates in achieving good hMC4R agonist potency and selectivity against hMC1R in linear pentapeptides.

MeSH terms

Amino Acid Sequence
Carboxylic Acids / chemistry*
Carboxylic Acids / pharmacology*
Cyclohexanes / chemistry*
Cyclohexanes / pharmacology*
Humans
Inhibitory Concentration 50
Molecular Structure
Receptor, Melanocortin, Type 1 / agonists*
Receptor, Melanocortin, Type 4 / agonists*
Sensitivity and Specificity
Substrate Specificity

Substances

1-amino-4-phenylcyclohexane-1-carboxylic acid
Carboxylic Acids
Cyclohexanes
Receptor, Melanocortin, Type 1
Receptor, Melanocortin, Type 4