ABSTRACT
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.
Subject(s)
Arginine/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Cell Line , Chromatography, High Pressure Liquid , Humans , Luciferases/genetics , Models, Molecular , Molecular Conformation , Structure-Activity RelationshipABSTRACT
We have prepared novel peptidomimetics based on a 2,4,6-trisubstituted tetrahydropyran. This scaffold was constructed in an isosteric transformation using conceptual constraints imposed on a tripeptide moiety involving O(i)'-C(i+1)(gamma) and O(i)'-N(i+2) formal cyclization modes. A series of regioselective transformations commencing with a substituted dihydropyran-4-one readily provided the required analogues. Specific tetrahydropyrane analogues modeled on PheArgTrp as a truncated version of the melanocortin receptor message sequence, showed activity at the melanocortin receptors MC4R and MC1R. Thus, the 2,4,6-trisubstituted tetrahydropyran scaffold has provided a potentially useful peptidomimetic lead, and conceptual cyclization of peptide moieties can offer a valuable design strategy in peptidomimetic research.
Subject(s)
Oligopeptides/chemistry , Pyrans/chemistry , Receptors, Melanocortin/drug effects , Arginine/chemistry , Biomimetic Materials , Cells, Cultured , Humans , Isomerism , Models, Chemical , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Peptides, Cyclic/chemistry , Peptides, Cyclic/metabolism , Phenylalanine/chemistry , Protein Binding , Pyrans/pharmacology , Receptors, Melanocortin/genetics , Tryptophan/chemistryABSTRACT
[reaction: see text] We have synthesized a series of 2,4,5-trisubstituted tetrahydropyran derivatives to determine the utility of this scaffold as a peptidomimetic platform. The key synthetic steps involved a palladium-mediated cross-coupling reaction of a dihydropyran-4-one moiety to introduce R(2) followed by a sequential regio- and diastereoselective reduction of sp(2) carbon centers. Selected compounds have shown biological activity at melanocortin receptors, indicating that this scaffold may be useful in the design of peptidomimetics relating to a tripeptide structure.
Subject(s)
Oligopeptides/chemistry , Pyrans/chemical synthesis , Pyrans/pharmacology , Receptors, Corticotropin/metabolism , Biomimetic Materials , Ligands , Models, Molecular , Oxidation-Reduction , Pyrans/chemistry , Receptors, Melanocortin , StereoisomerismABSTRACT
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. This cell line responds, by increasing luciferase expression, to a variety of skeletal muscle hypertrophy-inducing agents, including insulin, insulin-like growth factor I, testosterone, and the beta-adrenergic receptor agonist isoproterenol, in both the undifferentiated and differentiated states. This cell-based system should be useful for identifying novel hypertrophy-inducing agents as well as understanding hypertrophy signal transduction.
