| Abstract
| - Unique opioid mimetic substances containing identical N-terminal aromatic residues separatedby an unbranched alkyl chain containing two to eight methylene groups were developed.Regardless of the length of interposing alkyl chain, the bis-Tyr and bis-Phe compounds wereinactive; however, replacement by a single Dmt (2‘,6‘-dimethyl-l-tyrosine) residue enhancedactivity by orders of magnitude. Moreover, the bis-Dmt compounds were another 10-fold morepotent with an optimum intra-aromatic ring distance of about four to six methylene units.1,4-Bis(Dmt-NH)butane (7) had high μ-opioid receptor affinity (Ki = 0.041 nM) and functionalμ-opioid agonist bioactivity (IC50 = 5.3 nM) with in vivo central (intracerebroventricular) andsystemic (subcutaneous) analgesia in mice (1.5- to 2.5-fold greater than and 10−12% relativeto morphine, respectively); these activities were reversed by naloxone to the same degree. Itappears that the bis-Dmt compounds indiscriminately act as both message and address domains.
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