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BEHAVIORAL PHARMACOLOGY

Novel 2',6'-Dimethyl-L-Tyrosine-Containing Pyrazinone Opioid Mimetic µ-Agonists with Potent Antinociceptive Activity in Mice

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (Y.J., S.D.B., L.H.L.); Kobe Gakuin University, Nishi-ku, Kobe, Japan (Y.O., Y.T., K.S.); and Tohoku Pharmaceutical University, Aoba-ku, Sendai, Japan (Y.S., A.A.)

Novel bioactive opioid mimetic agonists containing 2',6'-dimethyl-L-tyrosine (Dmt) and a pyrazinone ring interact with µ-and -opioid receptors. Compound 1 [3-(4' -Dmt-aminobutyl)-6-(3'-Dmt-aminopropyl)-5-methyl-2(1H)pyrazinone] exhibited high µ-opioid receptor affinity and selectivity (K_iµ = 0.021 nM and K_i/K_iµ = 1,519, respectively), and agonist activity on guinea pig ileum (IC₅₀ = 1.7 nM) with weaker -bioactivity on mouse vas deferens (IC₅₀ = 25.8 nM). Other compounds (2-4) had µ-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 (-antagonist) partially blocked antinociception in the TF, but it was ineffective in the HP test, whereas -funaltrexamine (irreversible antagonist, µ₁/µ₂-subtypes) but not naloxonazine (µ₁-subtype) inhibited TF test antinociception, yet both blocked antinociception in the HP test. Our data indicated that 1 acted through µ- and -opioid receptors to produce spinal antinociception, although primarily through the µ₂-receptor subtype; however, the µ₁-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 µ-opioid receptors.

Address correspondence to: Dr. Yunden Jinsmaa, Medicinal Chemistry Group, Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709. E-mail: yunden{at}niehs.nih.gov