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Structure-activity relationship study of opiorphin, a human dual ectopeptidase inhibitor with antinociceptive properties.

Abstract：

:Toward developing new potential analgesics, this first structure-activity 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 Phe(3) is a key residue for neprilysin and aminopeptidase N (AP-N) ectoenkephalinase inhibition. A series of Phe(3)-halogenated analogues revealed that halogen bonding based optimization strategies are not applicable to this residue. Additional substituted Phe(3) derivatives showed that replacing l-Phe(3) for d-Phe(3) 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-π stacking interactions between the aromatic ring of d-Phe(3) and the Hγ protons of Arg(2). This structural motif is not possible for the native opiorphin and may be useful for the design of further potent and metabolically stable analogues.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Rosa M,Arsequell G,Rougeot C,Calle LP,Marcelo F,Pinto M,Centeno NB,Jiménez-Barbero J,Valencia G

doi

10.1021/jm2012112

subject

Has Abstract

pub_date

2012-02-09 00:00:00

pages

1181-8

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

杂志文章

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