Nascent structure-activity relationship study of a diastereomeric series of kappa opioid receptor antagonists derived from CJ-15,208

被引：30

作者：

Dolle, Roland E. ^{[1
]}

Michaut, Mathieu ^{[1
]}

Martinez-Teipel, Blanca ^{[1
]}

Seida, Pamela R. ^{[1
]}

Ajello, Christopher W. ^{[1
]}

Muller, Alison L. ^{[2
]}

DeHaven, Robert N. ^{[2
]}

Carroll, Patrick J. ^{[3
]}

机构：

[1] Adolor Corp, Dept Chem, Exton, PA 19341 USA

[2] Adolor Corp, Dept Mol Pharmacol, Exton, PA 19341 USA

[3] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 13期

关键词：

Cyclic tetrapeptide; CJ-15,208; Kappa opioid receptor antagonist; Mu opioid receptor antagonist; SAR; Structure-activity relationship; Opiate; MU-AGONIST/DELTA-ANTAGONIST; PHARMACOLOGICAL CHARACTERIZATION; COMBINATORIAL LIBRARY; PHYSICAL-DEPENDENCE; LIGANDS; DELTA; POTENT; TOLERANCE; MORPHINE; RATS;

D O I：

10.1016/j.bmcl.2009.04.105

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Cyclic tetrapeptide c[Phe-pro-Phe-trp] 2, a diastereomer of CJ-15,208 ( 1), was identified as a potent dual kappa/mu opioid receptor antagonist devoid of delta opioid receptor affinity against cloned human receptors: K(i) (2) = 3.8 nM (kappa), 30 nM (mu); IC(50) ([(35)S]GTP gamma S binding) = 140 nM (kappa), 21 nM (mu). The D-tryptophan residue rendered 2 ca. eightfold and fourfold more potent at kappa and mu, respectively, than the corresponding L-configured tryptophan in the natural product 1. Phe analogs 3-10, designed to probe the effect of substituents on receptor affinity and selectivity, possessed K(i) values ranging from 14 to 220 nM against the kappa opioid receptor with mu/kappa ratios of 0.45-3.0. An alanine scan of 2 yielded c[Ala-pro-Phe-trp] 12, an analog equipotent to 2. Agents 2 and 12 were pure antagonists in vitro devoid of agonist activity. Ac-pro-Phe-trpPhe-NH(2) 16 and Ac-Phe-trp-Phe-pro-NH(2) 17 two of the eight possible acyclic peptides derived from 1 and 2, were selective, modestly potent mu ligands: K(i) (16) = 340 nM (mu); K(i) (17) = 360 nM (mu). (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：3647 / 3650

页数：4

共 23 条

[21] The opioid μ agonist/δ antagonist DIPP-NH2[Ψ] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats [J].