Balboni Gianfranco, Fiorini Stella, Baldisserotto Anna, Trapella Claudio, Sasaki Yusuke, Ambo Akihiro, Marczak Ewa D, Lazarus Lawrence H, Salvadori Severo
Department of Toxicology, University of Cagliari, I-09124 Cagliari, Italy.
J Med Chem. 2008 Aug 28;51(16):5109-17. doi: 10.1021/jm800587e. Epub 2008 Aug 5.
Some reference opioids containing the Dmt-Tic pharmacophore, especially the delta agonists H-Dmt-Tic-Gly-NH-Ph (1) and H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid (4) (UFP-512) were evaluated for the influence of the substitution of Gly with aspartic acid, its chirality, and the importance of the -NH-Ph and N(1)H-Bid hydrogens in the inductions of delta agonism. The results provide the following conclusions: (i) Asp increases delta selectivity by lowering the mu affinity; (ii) -NH-Ph and N(1)H-Bid nitrogens methylation transforms the delta agonists into delta antagonists; (iii) the substitution of Gly with L-Asp/D-Asp in the delta agonist H-Dmt-Tic-Gly-NH-Ph gave delta antagonists; the same substitution in the delta agonist H-Dmt-Tic-NH-CH2-Bid yielded more selective agonists, H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid and H-Dmt-Tic-NH-(R)CH(CH2-COOH)-Bid; (iv) L-Asp seems important only in functional bioactivity, not in receptor affinity; (v) H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid(N(1)-Me) (10) evidenced analgesia similar to 4, which was reversed by naltrindole only in the tail flick. 4 and 10 had opposite behaviours in mice; 4 caused agitation, 10 gave sedation and convulsions.
对一些含有Dmt-Tic药效基团的参考阿片类药物，特别是δ激动剂H-Dmt-Tic-Gly-NH-Ph（1）和H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid（4）（UFP-512），评估了用天冬氨酸取代甘氨酸、其手性以及-NH-Ph和N(1)H-Bid氢原子在诱导δ激动作用中的重要性。结果得出以下结论：（i）天冬氨酸通过降低μ亲和力提高δ选择性；（ii）-NH-Ph和N(1)H-Bid氮原子甲基化将δ激动剂转变为δ拮抗剂；（iii）在δ激动剂H-Dmt-Tic-Gly-NH-Ph中用L-天冬氨酸/D-天冬氨酸取代甘氨酸得到δ拮抗剂；在δ激动剂H-Dmt-Tic-NH-CH2-Bid中进行相同取代产生了选择性更高的激动剂H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid和H-Dmt-Tic-NH-(R)CH(CH2-COOH)-Bid；（iv）L-天冬氨酸似乎仅在功能生物活性方面重要，在受体亲和力方面不重要；（v）H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid(N(1)-Me)（10）表现出与4相似的镇痛作用，仅在甩尾试验中被纳曲吲哚逆转。4和10在小鼠中表现出相反的行为；4引起躁动，10导致镇静和惊厥。
