A potent and selective endogenous agonist for the µ-opiate receptor

Peptides have been identified in mammalian brain that are considered to be endogenous agonists for the δ (enkephalins) and κ (dynorphins) opiate receptors, but none has been found to have any preference for the µ receptor1–3. Because morphine and other compounds that are clinically useful and open to abuse act primarily at the µ receptor4, 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 δ and κ receptors) for the µ, receptor. This peptide is more effective than the µ-selective analogue DAMGO in vitroand 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 µ receptor of any endogenous substance so far described and they maybe natural ligands for this receptor.