Identification and in Vivo and in Vitro Characterization of Long Acting and Melanocortin 4 Receptor (MC4-R) Selective 伪-Melanocyte-Stimulating Hormone (伪-MSH) Analogues

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• 作者：Kilian Conde-Frieboes ; Henning Th酶gersen ; Jesper F. Lau ; Ulrich Sensfuss ; Thomas K. Hansen ; Leif Christensen ; Jane Spetzler ; Helle B. Olsen ; Cecilia Nilsson ; Kirsten Raun ; Kirsten Dahl ; Birgit S. Hansen ; Birgitte S. Wulff
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：1969-1977
• 全文大小：294K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

We report in vitro and in vivo data of new 伪-melanocyte-stimulating hormone (伪-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 伪-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鈥揇awley rats after a single subcutaneous administration.