DMT-TIC-OH, a highly selective and potent delta-opioid dipeptide receptor antagonist after systemic administration in the mouse

被引:14
作者
Capasso, A
Guerrini, R
Balboni, G
Sorrentino, L
Temussi, P
Lazarus, LH
Bryant, SD
Salvadori, S
机构
[1] UNIV FERRARA, DEPT PHARMACEUT SCI, I-44100 FERRARA, ITALY
[2] UNIV NAPLES FEDERICO II, DEPT EXPTL PHARMACOL, NAPLES, ITALY
[3] UNIV NAPLES FEDERICO II, DEPT CHEM, NAPLES, ITALY
[4] NIEHS, RES TRIANGLE PK, NC 27709 USA
关键词
Dmt-Tic-OH; opioid dipeptide; antagonism; opioid receptors;
D O I
10.1016/0024-3205(96)00353-0
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Dmt-Tic-OH (DTOH) and Dmt-Tic-Ala-OH (DTAOH), effective antagonists in vitro, represent a new potent opioid dipeptides for the delta-opioid receptor (K-i delta of 0.022 nM and a selectivity, K-i mu/K-i delta, of 150,000 for DTOH; K-i delta of 0.285 nM and a selectivity K-i mu/K-i delta, of 20,4 for DTAOH). Ln the present study we considered the pharmacological activity of these two new delta opioid peptide receptor antagonists in vivo. Therefore, we have evaluated their possible antagonistic activity against the antinociception induced by the highly selective delta opioid receptor agonist, [D-Ala(2)]deltorphin II (DEL). Furthermore, these two delta opioid peptide receptor antagonists were injected centrally or peripherally in order to assess their ability to act also after systemic administration. Concurrent i.c.v. injection of DTOH or DTAOH (0.5-1.0-2.0 nM) with DEL (5 nmol) induced a significant reduction of DEL antinociception. By contrast, while DTOH (10-20-40 mg/kg) administered peripherally (i.p., s.c. or i.v.) was also able to reduce DEL antinociception, DTAOH failed. The present results indicate that DTOH is the first opioid dipeptide with delta antagonist activity after systemic administration and it could be important in the clinical and therapeutic applications.
引用
收藏
页码:PL93 / PL98
页数:6
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