A Convenient Asymmetric Synthesis of the Unnatural Amino Acid 2,6-Dimethyl-L-tyrosine

19) During the synthesis, Z-configuration of acetamidoacrylate after Heck reaction and L-configuration of the final phenylalanine analogues were confirmed by X-ray analysis.According to the Chart 1, L-phenylalanine analogues were prepared. The starting materials, 2-iodotoluene (1a; Sigma- Six phenylalanine analogues containing 2-methyl-, 2,6-dimethyl-, 2-ethyl-6-methyl-, 2-isopropyl-6-methyl-, 2,4,6-trimethyl-, and 3,5-dimethyl-L-phenylalanine were synthesized enantioselectively through asymmetric hydrogenation of acetamidoacrylate derivatives. Enzymatic digestion and X-ray analysis supported the L-configuration of the phenylalanine derivatives obtained.

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“…3 Hz 20) are consistent with the desired Z-configuration. 19) The Z-configuration of 2c was also confirmed by X-ray analysis (Fig. 1).…”

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confidence: 54%

“…The Heck reaction was employed to produce (Z)-dehydroamino acid derivatives (2a-f). 19) In this reaction, more than 95% Z-isomer over the corresponding E-isomer was constructed through a complex between substrate and catalyst. Addition of hexane to the condensed reaction mixture precipitated the desired pure Z-isomer.…”

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confidence: 99%

Enantioselective Synthesis of a Phenylalanine Library Containing Alkyl Groups on the Aromatic Moiety: Confirmation of Stereostructure by X-Ray Analysis

Tsuda

Minoura

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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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).…”

Section: Methodsmentioning

confidence: 99%

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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“…Materials: H-L-Dmt-OH was a generous gift from and synthetized by Dygos et al (8). H-Tic-OH was obtained from Bachem Feinchemikalien AG.…”

Section: Methodsmentioning

confidence: 99%

Tritiation of delta opioid-receptor selective antagonist dipeptide ligands with extraordinary affinity containing 2′, 6′dimethyltyrosine

et al. 1999

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Recently a new class of ~ opioid antagonists has been discovered by using Tyr-Tic sequence. The substitution of Tyr 1 by Dmt resulted in a new analogue (H-Dmt-Tic-OH) with enhanced affinity and selectivity. Because of its excellent property we chose it for labelling with tritium. At the same time peptides containing Tic at position 2 undergo spontaneous diketopiperazine formation in some solvents, and they lose some of their binding ability. To avoid this unwanted side-reaction we synthetized the N-methylated analogue (N,N(Me)2-Dmt-Tic-OH), and it was more stable under storage condition, but 5 affinity declined moderately. On the basis of this information we prepared diiodinated analogues of these dipeptides. Catalytic dehalotritiation of precursors resulted in tritiated peptides. High specific radioactivity, 44.67 Ci/mmol with [3H]Dmt-Tic-OH and 59.88 Ci/mmol with N,N(Me)2-[ 3H]Dmt-Tic-OH were achieved. IntroductionThe heterogeneity ofopioid receptors is well established and it is accepted that there are at least three types of opioid receptor (~t, 5 and K). As no opioid ligand has been found to exhibit absolute specificity for any particular receptor type, several labzoratories have made an effort to develop ligands that have as high specificity as possible. Recently opioid dipeptide antagonists containing tyrosine and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) (1) have been described for the 5 receptor. Replacement of Tyr by the more hydrophobic residue 2',6'-dimethyltyrosine (Dmt) resulted in new analogues. The peptide Dmt-Tic retained in vitro 5 opioid antagonism (2) and exhibit exceptional 5 receptor affinity (Ki5 = 0.022 nM) and extraordinary high selectivity (Ki~/Ki5 = 150000). One liability of small peptides is cyclization to a diketopiperazine during storage in acidic or some inorganic media (3,4,5). This reaction might decrease the activity ofligands. This phenomenon occurs not only for peptides containing Tic or other constrained residues at the C-terminus, but also with other amino acids (6). On the basis of these results we have synthetised N-alkylated analogue of Dmt-Tic with the purpose of avoiding the diketopiperazine formation (7). N,N-Dimethylation affected the 5 receptor binding properties and the affinity of N,N(Me)2-Dmt-Tic-OH moderately declined (5-fold) in comparison with that of H-Dmt-Tic-OH; however a 5 affinity (Ki5 = 0.118 nM) and selectivity of 20000 took it an exceptional opioid ligand.

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A Convenient Asymmetric Synthesis of the Unnatural Amino Acid 2,6-Dimethyl-L-tyrosine

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Enantioselective Synthesis of a Phenylalanine Library Containing Alkyl Groups on the Aromatic Moiety: Confirmation of Stereostructure by X-Ray Analysis

Enantioselective Synthesis of a Phenylalanine Library Containing Alkyl Groups on the Aromatic Moiety: Confirmation of Stereostructure by X-Ray Analysis

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

Tritiation of delta opioid-receptor selective antagonist dipeptide ligands with extraordinary affinity containing 2′, 6′dimethyltyrosine

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