Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics.
Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics.
复制标题
DOI：
10.1016/j.ejmech.2014.12.033
复制
发表时间：
2015-03-06
影响因子：
6.7
通讯作者：
Ballet, Steven
中科院分区：
文献类型：
--
作者：
Guillemyn, Karel;Kleczkowska, Patrycia;Lesniak, Anna;Dyniewicz, Jolanta;Van der Poorten, Olivier;Van den Eynde, Isabelle;Keresztes, Attila;Varga, Eva;Lai, Josephine;Porreca, Frank;Chung, Nga N.;Lemieux, Carole;Mika, Joanna;Rojewska, Ewelina;Makuch, Wioletta;Van Duppen, Joost;Przewlocka, Barbara;Vanden Broeck, Jozef;Lipkowski, Andrzej W.;Schiller, Peter W.;Tourwe, Dirk;Ballet, Steven
对已报道的混合阿片激动剂-神经激肽1受体(NK1R)拮抗剂4(DMT-D-Arg-Aba-Gly-(3‘，5’-(CF3)2)NME-BYyl)进行了修饰，以确定这两个药效团的重要特征。对新的双配体进行了体外测试，然后选择了两个化合物(DMT-D-Arg-Aba-β-Ala-Nme-Bn)进行了体内行为测试，并在大鼠急性(甩尾)和神经病理性疼痛(冷板和von Frey)模型上进行了测试。与母体阿片化合物33(没有NK1R药效团)相比，杂交22在神经病理性疼痛模型中更活跃。NK1R拮抗剂6可以减轻神经病理性疼痛。令人惊讶的是，尽管NK1R的体外活性低于NK1R，但化合物22在神经病理性疼痛模型中的活性更高。在大鼠神经病理性疼痛模型中，虽然观察到4和22有明显的镇痛作用，但在长期给药后，两者都表现出与吗啡相似的耐受性和与吗啡的交叉耐受性。
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-β-Ala-NMe-Bn) were selected for in vivo behavioral 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.
登录
查看更多内容
影响因子：
7.3
作者：
Ballet, Steven;Feytens, Debby;Buysse, Koen;Chung, Nga N.;Lemieux, Carole;Tumati, Suneeta;Keresztes, Attila;Van Duppen, Joost;Lai, Josephine;Varga, Eva;Porreca, Frank;Schiller, Peter W.;Broeck, Jozef Vanden;Tourwe, Dirk
通讯作者：
Tourwe, Dirk
DOI：
10.1073/pnas.130181897
发表时间：
2000-06-20
影响因子：
11.1
作者：
Foran, SE;Carr, DB;Kream, RM
通讯作者：
Kream, RM
影响因子：
2.7
作者：
Ballet, Steven;Feytens, Debby;Balboni, Gianfranco
通讯作者：
Balboni, Gianfranco
影响因子：
13.9
作者：
Costigan M;Scholz J;Woolf CJ
通讯作者：
Woolf CJ
影响因子：
--
作者：
Janecka, A;Poels, J;Vanden Broeck, J
通讯作者：
Vanden Broeck, J