Systemic and Spinal Analgesic Activity of a -Opioid-Selective Lanthionine Enkephalin Analog

A lanthionine enkephalin derivative, Tyr-c[D-ValL-Gly-Phe-DAlaL ]-OH (DVL DAL LanEnk), where ValL and AlaL denote the lanthionine amino acid ends linked via a monosulfide bridge to form the lanthionine structure, was synthesized. It was found to possess selectivity for and potency at the versus opioid receptor as defined by binding studies and by its respective activity on the mouse vas deferens compared with the guinea pig ileum. The agent produced a potent analgesia after intrathecal and intraperitoneal delivery with ED50 values being, respectively, 0.19 g and 0.49 mg/kg. The effects of the agent were reversed by the -selective antagonist naltrindole. These analgesic actions occurred at doses that had no effect upon general behavior or motor function. These results suggest a potent -preferring agent suitable for development as a systemic opioid analgesic. Agents that interact as agonists at the receptor produce a potent analgesia. Studies with intracerebral and intrathecal delivery have demonstrated that these effects are mediated by opioid binding sites in the brain and in the spinal cord in animals and in humans (Yaksh, 1997). Similarly, systemic delivery of agents known to cross the blood-brain barrier, e.g., the opioid alkaloids morphine and its congeners, will yield a potent antinociception that displays a pharmacology expected for receptors. The clinical relevance of this systemic activity is well appreciated and to date receptor agonists represent the mainstay of systemic pain therapy in humans. Comparable studies with opioid agonists have similarly demonstrated that receptor-preferring agonists can produce a potent analgesia after intrathecal delivery (Tung and Yaksh, 1982; Porreca et al., 1987). As the majority of opioids with selective affinity and efficacy for the site are peptides subject to poor blood-brain barrier penetration and relatively rapid degradation, the demonstration of the systemic activity of these agonists has been less rigorously approached. Recent efforts have been focused on developing opioid receptor agonists with an emphasis on nonpeptidic structures. Thus, molecules such as TAN-67 (Tseng et al., 1997), SNC-80 (Bilsky et al., 1995), and BW373U86 (Chang et al., 1993) have been reported to have selectivity and efficacy at the receptor and to show activity after systemic delivery. In our own work, after synthesizing a series of peptidomimetics containing enkephalin analogs and testing them for opioid activity and biostability (Baker et al., 2000; Goodman et al., 2001; Rew et al., 2002), we have arrived at a compound, Tyr-c[D-ValLGly-Phe-D-AlaL]-OH (DVL DAL LanEnk), that has significant selectivity and also in vivo activity. In this article, we report on the analgesic activities of this lanthionine enkephalin after systemic and intrathecal delivery. Materials and Methods These studies were carried out according to protocols approved by the Institutional Animal Care and Use Committee of the University of California, San Diego (La Jolla, CA).