Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - Neurokinin-1 antagonist peptidomimetics

被引：30

作者：

Guillemyn, Karel ^{[1
,2
]}

Kleczkowska, Patrycia ^{[5
,8
]}

Lesniak, Anna ^{[5
]}

Dyniewicz, Jolanta ^{[5
]}

Van der Poorten, Olivier ^{[1
,2
]}

Van den Eynde, Isabelle ^{[1
,2
]}

Keresztes, Attila ^{[3
]}

Varga, Eva ^{[3
]}

Lai, Josephine ^{[3
]}

Porreca, Frank ^{[3
]}

Chung, Nga N. ^{[4
]}

Lemieux, Carole ^{[4
]}

Mika, Joanna

Rojewska, Ewelina ^{[6
]}

Makuch, Wioletta ^{[6
]}

Van Duppen, Joost ^{[7
]}

Przewlocka, Barbara ^{[6
]}

Vanden Broeck, Jozef ^{[7
]}

Lipkowski, Andrzej W. ^{[5
]}

Schiller, Peter W. ^{[4
]}

Tourwe, Dirk ^{[1
,2
]}

Ballet, Steven ^{[1
,2
]}

机构：

[1] Vrije Univ Brussel, Dept Chem, Organ Chem Lab, B-1050 Brussels, Belgium

[2] Vrije Univ Brussel, Dept Bioengn Sci, B-1050 Brussels, Belgium

[3] Univ Arizona, Dept Pharmacol, Tucson, AZ 85724 USA

[4] Clin Res Inst Montreal, Dept Chem Biol & Peptide Res, Montreal, PQ H2W 1R7, Canada

[5] Polish Acad Sci, Med Res Ctr, Neuropeptide Lab, PL-02106 Warsaw, Poland

[6] Polish Acad Sci, Inst Pharmacol, Dept Pain Pharmacol, PL-31343 Krakow, Poland

[7] Univ Leuven KU Leuven, Anim Physiol & Neurobiol Dept, B-3000 Louvain, Belgium

[8] Med Univ Warsaw, Ctr Preclin Res & Technol CePT, Dept Pharmacodynam, Warsaw, Poland

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 92卷

关键词：

Hybrid peptides; Opioid agonism; NK1R antagonism; Acute pain; Neuropathic pain; Tolerance; PAINFUL DIABETIC-NEUROPATHY; 1 RECEPTOR ANTAGONIST; PHARMACOLOGICAL CHARACTERIZATION; ANTINOCICEPTIVE EFFICACY; MORPHINE-TOLERANCE; CHIMERIC PEPTIDE; IN-VITRO; ANALOGS; RAT; HYPERALGESIA;

D O I：

10.1016/j.ejmech.2014.12.033

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A reported mixed opioid agonist neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3 ',5 '-(CF3)(2))NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-beta-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：64 / 77

页数：14

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