Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics

被引：20

作者：

Betti, Cecilia ^{[1
]}

Starnowska, Joanna ^{[2
]}

Mika, Joanna ^{[2
]}

Dyniewicz, Jolanta ^{[3
]}

Frankiewicz, Lukasz ^{[1
]}

Novoa, Alexandre ^{[1
]}

Bochynska, Marta ^{[3
]}

Keresztes, Attila ^{[4
]}

Kosson, Piotr ^{[3
]}

Makuch, Wioletta ^{[2
]}

Van Duppen, Joost ^{[5
]}

Chung, Nga. N. ^{[6
]}

Broeck, Jozef Vanden ^{[5
]}

Lipkowski, Andrzej W. ^{[3
]}

Schiller, Peter W. ^{[6
]}

Janssens, Frans ^{[7
]}

Ceusters, Marc ^{[7
]}

Sommen, Francois ^{[7
]}

Meert, Theo ^{[7
]}

Przewlocka, Barbara ^{[2
]}

Tourwe, Dirk ^{[1
]}

Ballet, Steven ^{[1
]}

机构：

[1] Vrije Univ Brussel, Dept Organ Chem, Brussels, Belgium

[2] Polish Acad Sci, Inst Pharmacol, Krakow, Poland

[3] Polish Acad Sci, Med Res Ctr, Neuropeptide Lab, Warsaw, Poland

[4] Univ Arizona, Dept Pharmacol, Tucson, AZ 85721 USA

[5] Katholieke Univ Leuven, Anim Physiol & Neurobiol Dept, Leuven, Belgium

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

[7] Janssen Res & Dev, Beerse, Belgium

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 12期

基金：

加拿大健康研究院;

关键词：

Designed multiple ligands; opioid agonism; NK1; antagonism; acute pain; neuropathic pain; RECEPTOR ANTAGONISTS; BIOLOGICAL EVALUATION; TETRAPEPTIDE ANALOGS; IN-VITRO; LIGANDS; PEPTIDE; POTENT; MORPHINE; HYPERALGESIA; ACTIVATION;

D O I：

10.1021/acsmedchemlett.5b00359

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the mu- and delta-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds.

引用

页码：1209 / 1214

页数：6

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