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Research ArticleBEHAVIORAL PHARMACOLOGY

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

Yunden Jinsmaa, Yoshio Okada, Yuko Tsuda, Kimitaka Shiotani, Yusuke Sasaki, Akihiro Ambo, Sharon D. Bryant and Lawrence H. Lazarus
Journal of Pharmacology and Experimental Therapeutics April 2004, 309 (1) 432-438; DOI: https://doi.org/10.1124/jpet.103.060061
Yunden Jinsmaa
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Yoshio Okada
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Yuko Tsuda
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Kimitaka Shiotani
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Yusuke Sasaki
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Akihiro Ambo
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Sharon D. Bryant
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Lawrence H. Lazarus
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Abstract

Novel bioactive opioid mimetic agonists containing 2′,6′-dimethyl-l-tyrosine (Dmt) and a pyrazinone ring interact with μ-and δ-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 (Kiμ = 0.021 nM and Kiδ/Kiμ = 1,519, respectively), and agonist activity on guinea pig ileum (IC50 = 1.7 nM) with weaker δ-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 (δ-antagonist) partially blocked antinociception in the TF, but it was ineffective in the HP test, whereas β-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 δ-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.

Footnotes

  • DOI: 10.1124/jpet.103.060061.

  • ABBREVIATIONS: Dmt, 2′,6′-dimethyl-l-tyrosine; TF, tail-flick; HP, hot-plate; DPDPE, [d-Pen2,d-Pen5]-enkephalin; DAMGO, [d-Ala2,N-MePhe4,Gly5-ol]-enkephalin; GPI, guinea pig ileum; MVD, mouse vas deferens; NTI, naltrindole hydrochloride; NAZ, naloxonazine; β-FNA, β-funaltrexamine; HPLC, high-performance liquid chromatography; Boc, tert-butyloxycarbonyl; TFL, tail-flick latency; MED, minimum effective dose; AUC, area under the curve; ICI-154,129, N,N-diallyl-Tyr-Gly-ψ-(CH2)-Phe-Leu-OH.

    • Received September 15, 2003.
    • Accepted December 11, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 1
1 Apr 2004
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Research ArticleBEHAVIORAL PHARMACOLOGY

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

Yunden Jinsmaa, Yoshio Okada, Yuko Tsuda, Kimitaka Shiotani, Yusuke Sasaki, Akihiro Ambo, Sharon D. Bryant and Lawrence H. Lazarus
Journal of Pharmacology and Experimental Therapeutics April 1, 2004, 309 (1) 432-438; DOI: https://doi.org/10.1124/jpet.103.060061

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Research ArticleBEHAVIORAL PHARMACOLOGY

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

Yunden Jinsmaa, Yoshio Okada, Yuko Tsuda, Kimitaka Shiotani, Yusuke Sasaki, Akihiro Ambo, Sharon D. Bryant and Lawrence H. Lazarus
Journal of Pharmacology and Experimental Therapeutics April 1, 2004, 309 (1) 432-438; DOI: https://doi.org/10.1124/jpet.103.060061
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