Synthesis of Pyrazinone Ring-Containing Opioid Mimetics and Examination of Their Opioid Receptor-Binding Activity.

Okada, Yoshio; Fukumizu, Atsuko; Takahashi, M.; Tsuda, Yuko; Bryant, Sharon D.; Lazarus, Lawrence H.

doi:10.1248/cpb.47.1193

Cited by 7 publications

(8 citation statements)

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“…Analogues with inherently weak opioid receptor interactions or those published only with IC 50 values, in spite of their intrinsically high receptor activity56, 57 were not included in Tables II and III, although their functional bioactivities are found in Table IV ( 70–79 ). Furthermore, opioid analogues containing inactive Tyr58–61 or Phe cognates61 as well as 3′,5′‐diiodo‐ L ‐Tyr (Balboni et al, unpublished data), Dmt pseudopeptides lacking the heteroaromatic Tic nucleus,58 or a modified Tic aromatic ring,57, 62 C‐terminal extensions56, 58 or changes in chirality of the Dmt or Tic residues,63, 64 will not be discussed since they do not meet the defined criteria.…”

Section: Introductionmentioning

confidence: 99%

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem

Cramer

Karam

Bothwell

et al. 2002

J of Comparative Neurology

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Nucleus magnocellularis (NM) in the avian auditory brainstem receives auditory input from nerve the VIIIth and projects bilaterally to nucleus laminaris (NL). This projection preserves binaural segregation in that ipsilateral NM projects to dorsal dendrites of NL and contralateral NM projects to ventral dendrites of NL. We have begun to examine the molecular signals that influence segregation of inputs onto discrete regions of NL cells. We previously showed that the Eph receptor, EphA4, is expressed selectively in the dorsal NL neuropil from embryonic day (E) 9 to E11, when NM axons grow into the NL neuropil. This asymmetric distribution suggests that EphA4 acts as a guidance molecule during binaural segregation. We report here on the developmental changes in the expression of two other Eph receptors, EphB2 and EphB5, and two ligands, ephrin-B1 and ephrin-B2, in the chick auditory brainstem. These proteins are expressed in the auditory nuclei during the maturation of the NM-NL projection. EphB2, EphB5, and ephrin-B1 are expressed in dorsal and ventral NL neuropil and at the midline of the brainstem at E10-E12. At this age, ephrin-B2, a ligand for EphB receptors and for EphA4, is expressed in NL cell bodies and NM-NL axons. The expression of these proteins diminishs in the posthatch ages examined. These results suggest that several members of the Eph family are involved in maturation of the nuclei and their projections. Moreover, ephrin-B2 in growing axons may interact with the asymmetrically expressed EphA4 during the establishment of binaural segregation.

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Section: Introductionmentioning

confidence: 99%

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem

Cramer

Karam

Bothwell

et al. 2002

J of Comparative Neurology

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“…Briefly, the optical purity (Ͼ98%) of Dmt prepared as described previously (Dygos et al, 1992) was determined by HPLC using a chiral column [CROWNPAC CR(ϩ)] and reaction with D-amino acid and L-amino acid oxidases followed by amino acid analysis. Boc-Dmt-OH was prepared as described previously (Okada et al, 1999). The 3,6-bis-(Tyr-aminoalkyl)-5-methyl-2(1H)-pyrazinones were prepared by published procedures (Okada et al, 1999).…”

Section: Methodsmentioning

confidence: 99%

“…Boc-Dmt-OH was prepared as described previously (Okada et al, 1999). The 3,6-bis-(Tyr-aminoalkyl)-5-methyl-2(1H)-pyrazinones were prepared by published procedures (Okada et al, 1999). Boc-R(Z)-OH (R: Orn or Lys) coupled with H-RЈ(Z)-CH 2 Cl (RЈ: Orn or Lys) by a mixed anhydride procedure to yield Boc-R(Z)-RЈ(Z)-CH 2 Cl.…”

Section: Methodsmentioning

confidence: 99%

“…Boc-R(Z)-OH (R: Orn or Lys) coupled with H-RЈ(Z)-CH 2 Cl (RЈ: Orn or Lys) by a mixed anhydride procedure to yield Boc-R(Z)-RЈ(Z)-CH 2 Cl. The Boc groups were removed by hydrogen chloride in dioxane, and the amine HCl in MeOH or THF was refluxed for 1 h to give the protected pyrazinone derivatives, which were converted to the corresponding amines (Okada et al, 1999) by catalytic hydrogenation or by HBr/AcOH. The resulting amines were then coupled with Boc-Dmt-OH by using benzotriazolyloxytris(pyrrolidino)-phosphonium hexafluorophosphate reagent to produce the protected compounds 1 to 4.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we reported that symmetric opioidmimetic substances, which contain two identical Dmt residues separated by simple unbranched alkyl chain, are able to serve as both the message and address domains for binding to -opioid receptors . The cyclization of dipeptidyl chloromethyl ketones yielded pyrazinone derivatives, which can be easily inserted into an opioid peptide sequence (Okada et al, 1998(Okada et al, , 1999, leading to our synthesis of a new series of opioidmimetic substances containing Dmt.…”

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

Jinsmaa¹,

Okada²,

Tsuda³

et al. 2004

J Pharmacol Exp Ther

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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...

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Dmt and opioid peptides: A potent alliance

et al. 2003

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The introduction of the Dmt (2',6'-dimethyl-L-tyrosine)-Tic pharmacophore into the design of opioid ligands produced an extraordinary family of potent delta-opioid receptor antagonists and heralded a new phase in opioid research. First reviewed extensively in 1998, the incorporation of Dmt into a diverse group of opioid molecules stimulated the opioid field leading to the development of unique analogues with remarkable properties. This overview will document the crucial role played by this residue in the proliferation of opioid peptides with high receptor affinity (K(i) equal to or less than 1 nM) and potent bioactivity. The discussion will include the metamorphosis between delta-opioid receptor antagonists to delta-agonists based solely on subtle structural changes at the C-terminal region of the Dmt-Tic pharmacophore as well as their behavior in vivo. Dmt may be considered promiscuous due to the acquisition of potent mu-agonism by dermorphin and endomorphin derivatives as well as by a unique class of opioidmimetics containing two Dmt residues separated by alkyl or pyrazinone linkers. Structural studies on the Dmt-Tic compounds were enhanced tremendously by x-ray diffraction data for three potent and biologically diverse Dmt-Tic opioidmimetics that led to the development of pharmacophores for both delta-opioid receptor agonists and antagonists. Molecular modeling studies of other unique Dmt opioid analogues illuminated structural differences between delta- and mu-receptor ligand interactions. The future of these compounds as therapeutic applications for various medical syndromes including the control of cancer-associated pain is only a matter of time and perseverance.

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Synthesis of Pyrazinone Ring-Containing Opioid Mimetics and Examination of Their Opioid Receptor-Binding Activity.

Cited by 7 publications

References 0 publications

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem

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

Dmt and opioid peptides: A potent alliance

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