title: Discovery of corticotropin releasing factor 2 receptor selective sauvagine analogues for treatment of skeletal muscle atrophy.
abstract: The corticotropin release factor 2 receptor (CRF2R) has many biological activities including modulation of the stress response. Recently, we have demonstrated that CRF2R activation functions to prevent skeletal muscle wasting resulting from a variety of physiological stimuli. Thus we are interested in identifying CRF2R selective agonists with optimal pharmacological properties for use in treating muscle wasting diseases. Several CRF2R agonists are known including the frog peptide sauvagine (Svg), which display superior pharmacological properties compared to other CRF2R agonists. Unfortunately sauvagine is a nonselective CRFR agonist, thus making it of less utility due to side effects resulting from corticotropin release factor 1 receptor (CRF1R) activation. Because our initial modifications of Svg at position 11 improved CRF2R selectivity, we investigated the role of amino acids at positions 12 and 13 in Svg. We observed that phenylalanine, leucine, isoleucine, threonine, glutamine, histidine, and tyrosine at the 12th position were the strongest promoters of CRF2R selectivity whereas phenylalanine, glutamine, trytophane, tyrosine, valine, isoleucine, leucine, and 2-naphthylalanine were the preferred residues at the 13th position. Selective sauvagine peptides demonstrated improved antiatrophy effects in a mouse-casting model when compared to sauvagine itself. Thus, we demonstrate that the CRF2R selectivity can be improved by optimizing amino acids at positions 12 and 13 (all with proline at position 11) and that the selective sauvagine analogues demonstrate better in vivo efficacy than sauvagine itself.
authors.affiliation: Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA. isfort.rj@pg.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Isfort
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Michelle
authors.initials: M
authors.lastname: Tscheiner
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Donnelly
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Bauer
authors.forename: Frank
authors.initials: F
authors.lastname: Lefever
authors.forename: Richard T
authors.initials: RT
authors.lastname: Hinkle
authors.forename: Adam W
authors.initials: AW
authors.lastname: Mazur
mesh_terms: D019943:Amino Acid Substitution; D029845:Amphibian Proteins; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051379:Mice; D020966:Muscular Disorders, Atrophic / Q000188:drug therapy*; D036361:Peptide Hormones; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013977:Tibia / Q000187:drug effects
chemical_list: D029845:Amphibian Proteins; C101531:CRF receptor type 2; C101518:CRF(2alpha) receptor; D036361:Peptide Hormones; D010455:Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; C025727:sauvagine