Potent Dmt-Tic pharmacophoric δ- and μ-opioid receptor antagonists
Potent Dmt-Tic pharmacophoric δ- and μ-opioid receptor antagonists
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DOI：
10.1021/jm050377l
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发表时间：
2005-12-15
影响因子：
7.3
通讯作者：
Okada, Y
中科院分区：
文献类型：
--
作者：
Li, TY;Fujita, Y;Okada, Y
一系列二聚Dmt-Tic（2 '，6'-二甲基-L-酪氨酰基-1，2，3，4-四氢异喹啉-3-羧酸）类似物（8-14，18-22）通过二氨基烷烃和对称或不对称的3，6-二氨基烷基-2（1H）-吡嗪酮部分共价连接。所有化合物对6-阿片受体[K（6）= 0.06-1.53 nM]和γ-阿片受体[Ki（μ）= 1.37 - 5.72 nM]均表现出高亲和力，导致中等δ-受体选择性[Ki（μ）/Ki（δ）= 3-46]。无论Dmt-Tic药效团之间的接头类型如何，δ-阿片样物质介导的拮抗作用在所有类似物中都非常高（pA（2）= 10.42-11.28），而体外激动作用（MVD和GPI生物测定）基本上不存在（约100）。3至> 10 μ M）。虽然未修饰的N-末端（9，13，18）显示出弱的μ-阿片样物质拮抗作用（pA（2）= 6.78-6.99），但对μ-阿片样物质相关激动作用有负面影响的N，N '-二甲基化（21，22）（Balboni等人，Bioorg. 2003，11，5435-5441），显著增强μ-阿片样物质拮抗作用（对于21和22，PA（2）分别= 8.34和7.71），而不影响β-阿片样物质活性。这些数据是第一个证据表明，一个单一的二聚体阿片样物质配体含有Dmt-Tic药效团表现出高度有效的6-andy-阿片样物质拮抗剂活性。
A series of dimeric Dmt-Tic (2',6'-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) analogues (8-14, 18-22) were covalently linked through diaminoalkane and symmetric or asymmetric 3,6-diaminoalkyl-2(1H)-pyrazinone moieties. All the compounds exhibited high affinity for both 6-opioid receptors K(6) = 0.06-1.53 nM] andy-opioid receptors [K-i(mu) = 1.375.72 nM], resulting in moderate delta-receptor selectivity [K-i(mu)/K-i(delta) = 3-46]. Regardless of the type of linker between the Dmt-Tic pharmacophores, delta-opioid-mediated antagonism was extraordinarily high in all analogues (pA(2) = 10.42-11.28), while in vitro agonism (MVD and GPI bioassays) was essentially absent (ca. 3 to > 10 mu M). While an unmodified N-terminus (9, 13, 18) revealed weaku-opioid antagonism (pA(2) = 6.78-6.99), N,N'-dimethylation (21, 22), which negatively impacts on mu-opioid-associated agonism (Balboni et al., Bioorg. Med. Chem. 2003, 11, 5435-5441), markedly enhanced mu-opioid antagonism (pA(2) = 8.34 and 7.71 for 21 and 22, respectively) without affecting 6-opioid activity. These data are the first evidence that a single dimeric opioid ligand containing the Dmt-Tic pharmacophore exhibits highly potent 6- andy-opioid antagonist activities.