Structure鈥揂ctivity Relationship Study of Opiorphin, a Human Dual Ectopeptidase Inhibitor with Antinociceptive Properties

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• 作者：M貌nica Rosa ; Gemma Arsequell ; Catherine Rougeot ; Luis P. Calle ; Filipa Marcelo ; Marta Pinto ; Nuria B. Centeno ; Jes煤s Jim茅nez-Barbero ; Gregorio Valencia
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 9, 2012
• 年：2012
• 卷：55
• 期：3
• 页码：1181-1188
• 全文大小：375K
• 年卷期：v.55,no.3(February 9, 2012)
• ISSN：1520-4804

文摘

Toward developing new potential analgesics, this first structure鈥揳ctivity relationship study of opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH), a human peptide inhibiting enkephalin degradation, was performed. A systematic Ala scanning proved that Phep>3p> is a key residue for neprilysin and aminopeptidase N (AP-N) ectoenkephalinase inhibition. A series of Phep>3p>-halogenated analogues revealed that halogen bonding based optimization strategies are not applicable to this residue. Additional substituted Phep>3p> derivatives showed that replacing pan class="smallcaps">lpan>-Phep>3p> for pan class="smallcaps">dpan>-Phep>3p> increased the AP-N inhibition potency by 1 order of magnitude. NMR studies and molecular mechanics calculations indicated that the improved potency may be due to CH鈭捪€ stacking interactions between the aromatic ring of pan class="smallcaps">dpan>-Phep>3p> and the H纬 protons of Argp>2p>. This structural motif is not possible for the native opiorphin and may be useful for the design of further potent and metabolically stable analogues.