Zadina J E, Hackler L, Ge L J, Kastin A J
Veterans Affairs Medical Center, New Orleans, Louisiana 70146, USA.
Nature. 1997 Apr 3;386(6624):499-502. doi: 10.1038/386499a0.
Peptides have been identified in mammalian brain that are considered to be endogenous agonists for the delta (enkephalins) and kappa (dynorphins) opiate receptors, but none has been found to have any preference for the mu receptor. Because morphine and other compounds that are clinically useful and open to abuse act primarily at the mu receptor, it could be important to identify endogenous peptides specific for this site. Here we report the discovery and isolation from brain of such a peptide, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has a high affinity (Ki = 360 pM) and selectivity (4,000- and 15,000-fold preference over the delta and kappa receptors) for the mu receptor. This peptide is more effective than the mu-selective analogue DAMGO in vitro and it produces potent and prolonged analgesia in mice. A second peptide, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), which differs by one amino acid, was also isolated. The new peptides have the highest specificity and affinity for the mu receptor of any endogenous substance so far described and they may be natural ligands for this receptor.
在哺乳动物大脑中已鉴定出一些肽类，它们被认为是δ（脑啡肽）和κ（强啡肽）阿片受体的内源性激动剂，但尚未发现对μ受体有任何偏好性的肽。由于吗啡和其他临床上有用且易被滥用的化合物主要作用于μ受体，因此鉴定针对该位点的内源性肽可能很重要。在此我们报告从大脑中发现并分离出这样一种肽，即内吗啡肽-1（Tyr-Pro-Trp-Phe-NH2），它对μ受体具有高亲和力（Ki = 360 pM）和选择性（对δ和κ受体的偏好性分别为4000倍和15000倍）。该肽在体外比μ选择性类似物DAMGO更有效，并且在小鼠中产生强效且持久的镇痛作用。还分离出了第二种肽，内吗啡肽-2（Tyr-Pro-Phe-Phe-NH2），它与内吗啡肽-1仅相差一个氨基酸。迄今为止，这两种新肽对μ受体具有任何内源性物质中最高的特异性和亲和力，它们可能是该受体的天然配体。
