Opioid receptor selectivity alteration by single residue replacement: Synthesis and activity profile of [Dmt]deltorphin B

被引:45
作者
Guerrini, R
Capasso, A
Sorrentino, L
Anacardio, R
Bryant, SD
Lazarus, LH
Attila, M
Salvadori, S
机构
[1] UNIV FERRARA, DIPARTIMENTO SCI FARMACEUT, I-44100 FERRARA, ITALY
[2] UNIV SALERNO, SCH PHARM, I-84084 SALERNO, ITALY
[3] UNIV NAPLES FEDERICO II, DEPT EXPTL PHARMACOL, I-80131 NAPLES, ITALY
[4] DOMPE SPA, I-67100 LAQUILA, ITALY
[5] NIEHS, RES TRIANGLE PK, NC 27709 USA
[6] HELSINKI UNIV, DEPT PHARMACOL, DIV PHARMACOL & TOXICOL, SF-00014 HELSINKI, FINLAND
关键词
antinociception; bioassay; deltorphin; opioid receptor; peptide synthesis;
D O I
10.1016/0014-2999(96)00067-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The single amino acid replacement of 2',6'-dimethyl-L-tyrosine in deltorphin B (H-Dmt-D-Ala-Phe-Glu-Val-Val-Gly-NH2) yielded high affinity for mu- and delta-binding sites. [Dmt(1)]Deltorphin B lacks activity at kappa-opioid binding sites. Bioactivity in vitro with guinea-pig ileum confirmed that [Dmt(1)]deltorphin B interacted with mu-opioid receptors by reducing electrically induced contractions in a naloxone-reversible manner and was 150-fold more potent than morphine and comparable to [D-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAGO). The inhibition of spontaneous contractions of rabbit jejunum provided evidence for delta-opioid receptor interaction. Analgesia (hot plate and tail flick tests) revealed that [Dmt(1)]deltorphin B was 180- to 200-fold more potent than morphine. Pretreatment with naloxone, naltrindole or H-Dmt-Tic-Ala-OH (a highly selective delta-opioid receptor antagonist) prevented [Dmt(1)]deltorphin B antinociception. Thus, [Dmt(1)]deltorphin B exhibited remarkably high dual affinity and bioactivity toward delta- and mu-opioid receptors.
引用
收藏
页码:37 / 42
页数:6
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