Author/Authors :
Christopher Fotsch، نويسنده , , Duncan M. Smith، نويسنده , , Jeffrey A. Adams، نويسنده , , Janet Cheetham، نويسنده , , Michael Croghan، نويسنده , , Elizabeth M. Doherty، نويسنده , , Clarence Hale، نويسنده , , Mark A. Jarosinski، نويسنده , , Michael G. Kelly، نويسنده , , Mark H. Norman، نويسنده , , Nuria A. Tamayo، نويسنده , , Ning Xi، نويسنده , , James W. Baumgartner، نويسنده ,
Abstract :
The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro- Phe-Arg-Trp-Lys]-NH2 (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, Phe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC50 and EC50 below 10 nM. Compound 2a also showed 36- and 7-fold selectivity over MC3R and MC1R, respectively, in the binding assays. Subtle changes in cyclohexane stereochemistry and removal of functional groups led to analogues with lower affinity for the MC receptors.
