title: Identification and in vivo and in vitro characterization of long acting and melanocortin 4 receptor (MC4-R) selective α-melanocyte-stimulating hormone (α-MSH) analogues.
abstract: We report in vitro and in vivo data of new α-melanocyte-stimulating hormone (α-MSH) analogues which are N-terminal modified with a long chain fatty acid derivative. While keeping the pharmacophoric motif (d-Phe-Arg-Trp) fixed, we tried to improve selectivity and physicochemical parameters like solubility and stability of these analogues by replacing amino acids further away from the motif. Receptor specific changes in binding affinity to the melanocortin receptors were observed between the acetyl derivatives and the fatty acid analogues. Furthermore, amino acids at the N-terminal of α-MSH (Ser-Tyr-Ser) not considered to be part of the pharmacophore were found to have an influence on the MC4/MC1 receptor selectivity. While the acetyl analogues have an in vivo effect for around 7 h, the long chain fatty acid analogues have an effect up to 48 h in an acute feeding study in male Sprague-Dawley rats after a single subcutaneous administration.
authors.affiliation: Protein & Peptide Chemistry, Novo Nordisk, Novo Nordisk Park, 2760 Måløv, Denmark. kcf@novonordisk.com
authors.forename: Kilian
authors.initials: K
authors.lastname: Conde-Frieboes
authors.forename: Henning
authors.initials: H
authors.lastname: Thøgersen
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Lau
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sensfuss
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hansen
authors.forename: Leif
authors.initials: L
authors.lastname: Christensen
authors.forename: Jane
authors.initials: J
authors.lastname: Spetzler
authors.forename: Helle B
authors.initials: HB
authors.lastname: Olsen
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nilsson
authors.forename: Kirsten
authors.initials: K
authors.lastname: Raun
authors.forename: Kirsten
authors.initials: K
authors.lastname: Dahl
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Hansen
authors.forename: Birgitte S
authors.initials: BS
authors.lastname: Wulff
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005227:Fatty Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D012995:Solubility; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D019440:Anti-Obesity Agents; D005227:Fatty Acids; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH