Novel 2',6'-dimethyl-L-tyrosine-containing pyrazinone opioid mimetic mu-agonists with potent antinociceptive activity in mice.

Novel bioactive opioid mimetic agonists containing 2',6'-dimethyl-l-tyrosine (Dmt) and a pyrazinone ring interact with mu- and delta-opioid receptors. Compound 1 [3-(4' -Dmt-aminobutyl)-6-(3'-Dmt-aminopropyl)-5-methyl-2(1H)pyrazinone] exhibited high mu-opioid receptor affinity and selectivity (K(i)mu = 0.021 nM and K(i)delta/K(i)mu = 1,519, respectively), and agonist activity on guinea pig ileum (IC(50) = 1.7 nM) with weaker delta-bioactivity on mouse vas deferens (IC(50) = 25.8 nM). Other compounds (2-4) had mu-opioid receptor affinities and selectivities 2- to 5-fold and 4- to 7-fold less than 1, respectively. Intracerebroventricular administration of 1 in mice exhibited potent naloxone reversible antinociception (65 to 71 times greater than morphine) in both tail-flick (TF) and hot-plate (HP) tests. Distinct opioid antagonists had differential effects on antinociception: naltrindole (delta-antagonist) partially blocked antinociception in the TF, but it was ineffective in the HP test, whereas beta-funaltrexamine (irreversible antagonist, mu(1)/mu(2)-subtypes) but not naloxonazine (mu(1)-subtype) inhibited TF test antinociception, yet both blocked antinociception in the HP test. Our data indicated that 1 acted through mu- and delta-opioid receptors to produce spinal antinociception, although primarily through the mu(2)-receptor subtype; however, the mu(1)-receptor subtype dominates supraspinally. Subcutaneous and oral administration indicated that 1 crossed gastrointestinal and blood-brain barriers to produce central nervous system-mediated antinociception. Furthermore, daily s.c. dosing of mice with 1 for 1 week developed tolerance in a similar manner to that of morphine in TF and HP tests, implicating that 1 also acts through a similar mechanism analogous to morphine at mu-opioid receptors.