Neuropeptides--molecular Mechanism Of Action

工作总结：由通式H-Dmt-Tic-NH-CH（R）-R '组成的肽的有效δ-阿片受体拮抗剂家族测试了接头（烷基、Asp、Asn）（R）的长度和组成以及Tic的C-末端处羧酸酯基团相对于Bid（（1H-苯并咪唑-2-基）（R'））的位置。所有化合物都表现出高δ亲和力（Ki < 0.1 nM）;一些类似物具有高μ亲和力（Ki < 1 nM），这取决于羧酸酯的存在或不存在。几种含Bid类似物的生物活性具有δ激动作用;在这些类似物中检测到低至非常低的μ激动作用。数据验证了以下内容：接头的手性是无效的;负电荷影响μ亲和力;接头长度对于δ激动剂或拮抗剂活性的出现是关键的;并且来自Bid的C末端延伸也影响这些活性的获得。Dmt是所有这些活动的关键残留物。合成了一系列新的含Dmt的类似物，其含有由烷基链分开的双Dmt，具有非常高的μ亲和力（Ki < 0.1 nM），Ke = 3-5 nM，并且在体内与吗啡等效，而前者约为0.5 nM。比吗啡强25倍。对吡嗪酮形成的化学研究表明，在催化氢化过程中发生的与1，2-二氢吡嗪-2-酮衍生物连接的氨甲基的立即脱氨基反应具有高度的位点特异性。对Dmt掺入到内吗啡肽-2类似物中的效果进行了详细的研究，验证了含有Dmt的三肽或四肽是高度有效的，并且C-末端苯乙基可以取代Phe-酰胺。此外，Dmt-Pro键呈顺式构型。

Summary of Work: The potent delta-opioid receptor anatgonist family of peptides, consisting of the general formula H-Dmt-Tic-NH-CH(R)-R', tested the length and composition of the linker (alkyl, Asp, Asn) (R) and the position of the carboxylate group relative to Bid ((1H-benzimidazole-2-yl) (R') at the C-terminus of Tic. All the compounds exhibited high delta affinities (Ki < 0.1 nM); some analogues had high mu affinities (Ki < 1 nM) depending on the presence or absence of the carboxylate. The bioactivity of several Bid-containing analogues had delta agonism; low to very low mu agonism was detected in these analogues. The data verified the following: chirality of the linker is ineffective; a negative charge affects mu affinity; linker length is critical for the appearance of delta agonist or antagonist activity; and C-terminal extension from Bid also affects the acquisition of these activities. Dmt is the key residue for all these activities. A new series of synthetic Dmt-containing analogues contained bis-Dmt separated by alkyl chains was developed with very high mu affinities (Ki < 0.1 nM), Ke = 3-5 nM, and equipotent with morphine in vivo while the former are ca. 25 times more potent than morphine. Chemical studies on pyrazinone formation revealed an immediate deamination reaction from the aminomethyl group attached to the 1,2-dihyropyrazin-2-one derivative occurred during catalyic hydrogenation was highly site specific. A detailed study on the effect of Dmt incorporation into endomorphin-2 analogues was conducted that verified that the tri- or tetrapeptide containing Dmt was highly potent and that a C-terminal phenethyl group could substitute for Phe-amide. Furthermore, the Dmt-Pro bond was in the cis configuration.