MCH-R1 antagonists based on an arginine scaffold: SAR studies on the amino-terminus.

We have identified a novel series of potent MCH-R1 antagonists based on l-arginine. As predicted by computational methods, there was an activity dependence on the pi-electronic character of the aromatic systems corresponding to the amino-terminus of these molecules. These results have enhanced our understanding of the MCH-R1 receptor and the potential for a predictive homology model.

End-capping of the modified melanocortin tetrapeptide (p-Cl)Phe-D-Phe-Arg-Trp-NH2 as a route to hMC4R agonists.

Of the 42 R'-X-(p-Cl)Phe-D-Phe-Arg-Trp-NH(2) (X=CO, SO(2), PO, PS) tested at the human (h)MC1, hMC3, and hMC4 receptors (R), the most potent MC4R agonists (EC(50) of 8-20 nM) were obtained by end-capping with R'=CH(2)CHCH(2) (9), NCCH(2) (16), NH(2)COCH(2) (17), HCONHCH(2) (18), CH(3)NH (19), CH(2)CHCH(2)NH (21), 2-Th (23), PhCH(2) (30) and X=CO. These compounds possess 35-60-fold hMC4 versus hMC1Rs selectivity with urea LK-71 (19) being the most potent at hMC4R and MC4/1R selective (EC(50)=8.5 nM, MC4/1R=100).

Analogs of sub-nanomolar hMC1R agonist LK-184 [Ph(CH2)3CO-His-D-Phe-Arg-Trp-NH2]. An additional binding site within the human melanocortin receptor 1?

Twenty nine analogs of a superpotent MC1R agonist LK-184 (1) were tested at human melanocortin receptors (hMC1, hMC3, and hMC4Rs). All derivatives with the spacer between the N-terminus and the aromatic ring longer or shorter than C(3) were much less potent at hMC1R than 1. Only LK-312 PhCO(CH(2))(3)CO-His-d-Phe-Arg-Trp-NH(2) (3), partially mimicking the pi-system of 1, had an EC(50) of 0.

A novel cell-based system for evaluating skeletal muscle cell hypertrophy-inducing agents.

Skeletal muscle is a tissue that adapts to increased use by increasing contractile protein gene expression and ultimately skeletal muscle mass (hypertrophy). To identify hypertrophy-inducing agents that may be potentially useful in the treatment of age-related muscle loss (sarcopenia) and to better understand hypertrophy signal transduction pathways, we have created a skeletal muscle cell-based hypertrophy-responsive system. This system was created by permanently modifying the relatively undifferentiated C2C12 cell line so that it contains the beta-myosin heavy chain (beta-MHC) gene promoter and enhancer regions fused to a luciferase reporter gene.

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

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).