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

Abstract

Novel bioactive opioid mimetic agonists containing 2Ј,6Ј-dimethyl-L-tyrosine (Dmt) and a pyrazinone ring interact withand ␦-opioid receptors. Compound 1 [3-(4Ј-Dmt-aminobutyl)-6-(3Ј-Dmt-aminopropyl)-5-methyl-2(1H)pyrazinone] exhibited high -opioid receptor affinity and selectivity (K i ϭ 0.021 nM and K i ␦/K i ϭ 1,519, respectively), and agonist activity on guinea pig ileum (IC 50 ϭ 1.7 nM) with weaker ␦-bioactivity on mouse vas deferens (IC 50 ϭ 25.8 nM). Other compounds (2-4) had -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, 1 / 2 -subtypes) but not naloxonazine ( 1 -subtype) inhibited TF test antinociception, yet both blocked antinociception in the HP test. Our data indicated that 1 acted through -and ␦-opioid receptors to produce spinal antinociception, although primarily through the 2 -receptor subtype; however, the 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 -opioid receptors.Since the discovery of the endogenous opioid pentapeptides, [Met 5 ]-and [Leu 5 ]-enkephalin (Hughes et al., 1975), many peptide and nonpeptide compounds were synthesized in a search for greater receptor selectivity, stability, and potent bioactivity. Although all known endogenous and exogenous -, ␦-, and -opioid receptor peptides have distinct structural diversity, they share a common message domain, which is considered important for recognition by opioid receptors. This message region consists of a tyrosine residue, an N-terminal amino group, and a spacer (D-Ala, D-Met, Pro, or Gly-Gly) between the tyrosine and second aromatic ring, usually Phe, or Trp in the endomorphins (Zadina et al., 1997). The address domain, which is responsible for the biological response, contains the second aromatic ring and residues C-terminal thereafter. Message and address domains of opioid peptides represent distinct starting points for the design and development of novel opioid mimetics. For example, studies on opioid peptides showed that the substitution of the N-terminal tyrosine by 2Ј,6Ј-dimethyl-L-tyrosine (Dmt) dramatically increased receptor affinity in numerous peptides and enhanced their antinociceptive effect (Chandrakumar et al., 1992;Hansen et al., 1992;Pitzele et al., 1994;Guerri...

Antinociceptive activity of methanol extract of fruits of Capparis ovata in mice

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Antinociceptive, genotoxic and histopathological study of Heliopsis longipes S.F. Blake in mice

“…HLEE also showed important antinociceptive effect on the hotplate test. This assay shows activity in thermally sensitive afferent fibers, and activity of A␦ and C fibers (Jinsmaa et al, 2004). The highest doses of HLEE (30 and 100 mg/kg) significantly increased (56.6-58.9%) the response latency after 15 min.…”

Antinociceptive activity of methanol extract of flowers of Impatiens balsamina

“…The hot plate demonstrates supraspinal reflex mediated by m 1 -and m 2 -opioid receptors while the tail immersion monitors a spinal reflex involving m 2 -and d-opioid receptors (Jinsmaa et al, 2005(Jinsmaa et al, , 2004Arslan and Bektas, 2010). The findings of the present study indicate that the central antinociceptive effect of MIB may be due to its effect on m-opioid receptors of spinal as well as supraspinal system.…”