82317-87-1Relevant academic research and scientific papers
Bifunctional [2′,6′-dimethyl-L-tyrosine1] endomorphin-2 analogues substituted at position 3 with alkylated phenylalanine derivatives yield potent mixed μ-agonist/δ-antagonist and dual μ-agonist/δ-agonist opioid ligands
Li, Tingyou,Shiotani, Kimitaka,Miyazaki, Anna,Tsuda, Yuko,Ambo, Akihiro,Sasaki, Yusuke,Jinsmaa, Yunden,Marczak, Ewa,Bryant, Sharon D.,Lazarus, Lawrence H.,Okada, Yoshio
, p. 2753 - 2766 (2008/02/07)
Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2) and [Dmt1]EM-2 (Dmt = 2′,6′-dimethyl-L-tyrosine) analogues, containing alkylated Phe3 derivatives, 2′-monomethyl (2, 2′), 3′,5′- and 2′,6′-dimethyl (3, 3′, and 4′, respectively), 2′,4′,6′-trimethyl (6, 6′), 2′-ethyl-6′-methyl (7, 7′), and 2′-isopropyl-6′- methyl (8, 8′) groups or Dmt (5, 5′), had the following characteristics: (i) [Xaa3]EM-2 analogues exhibited improved μ- and δ-opioid receptor affinities. The latter, however, were inconsequential (Kiδ = 491-3451 nM). (ii) [Dmt 1,-Xaa3]EM-2 analogues enhanced μ- and δ-opioid receptor affinities (Kiμ = 0.069-0.32 nM; K iδ = 1.83-99.8 nM) without κ-opioid receptor interaction. (iii) There were elevated μ-bioactivity (IC50 = 0.12-14.4 nM) and abolished δ-agonism (IC50 > 10 μM in 2′, 3′, 4′, 5′, 6′), although 4′ and 6′ demonstrated a potent mixed μ-agonism/δ-antagonism (for 4′, IC50μ = 0.12 and pA2 = 8.15; for 6′, IC50μ = 0.21 nM and pA2 = 9.05) and 7′ was a dual μ-agonist/δ-agonist (IC50 μ = 0.17 nM; IC50δ = 0.51 nM).
Enantioselective syntheses of conformationally rigid, highly lipophilic mesityl-substituted amino acids
Medina, Eva,Moyano, Albert,Pericas, Miquel A.,Riera, Antoni
, p. 972 - 988 (2007/10/03)
Three N-Boc-protected amino acids substituted with a mesityl (=2,4,6- trimethylphenyl) group were synthesized in enantiomerically pure form, either by asymmetric epoxidation or by aminohydroxylation as the source of chirality. The 3-mesityloxirane-2-methanol 7, easily available in high enantiomer purity by Sharpless epoxidation, was converted into 3-{[(tert- butoxy)carbonyl]amino}-3-mesitylpropane-1,2-diol 9 by a regio- and stereoselective ring opening with an ammonia equivalent (sodium azide or benzhydrylamine), followed by hydrogenation and in situ treatment with (Boc)2O (Boc=[(tert-butoxy)carbonyl]) (Scheme 3). Oxidative cleavage of the diol fragment in 9 afforded N-[(tert-butoxy)carbonyl]-α-mesitylglycine 1 of >99% ee. This amino acid was also prepared in enantiomerically pure form starting from 2,4,6-trimethylstyrene (11) by a regioselective Sharpless asymmetric aminohydroxylation, followed by a 2,2,6,6-tetramethylpiperidin-1- yloxyl (TEMPO)-catalyzed oxidation (Scheme 4). On the other hand, 1-[(tert- butoxy)carbonyl]-2-{{[(tert-butyl)dimethylsilyl]oxy}methyl}-3- mesitylaziridine 14 was prepared from 9 by a sequence involving selective protection of the primary alcohol (as a silyl ether), activation of the secondary alcohol as a mesylate, and base-induced (NaH) cyclization (Scheme 5). The reductive cleavage of the aziridine ring (H2, Pd/C), followed by alcohol deprotection (Bu4NF/THF) and oxidation (pyridinium dichromate (PDC)/DMF or (TEMPO)/NaClO) provided, in high yield and enantiomeric purity, N-[(tert-butoxy)carbonyl]-β-mesitylalanine 2. Alternatively, the regioselective ring opening of the aziridine ring of 14 with lithium dimethylcuprate, followed by silyl-ether cleavage and oxidation lead to N- [(tert-butoxy)carbonyl]-β-mesityl-β-methylalanine 3. A conformational study of the methyl esters of the N-Boc-protected amino acids 1 and 3 carried out by variable-temperature 1H-NMR and semi-empirical (AM1) calculations shows the strong rotational restriction imposed by the mesityl group.
THE ANALOGS OF 8>VASOPRESSIN WITH DI- AND TRISUBSTITUTED PHENYLALANINE IN POSITION 2; SYNTHESIS AND SOME BIOLOGICAL PROPERTIES
Zertova, Miroslava,Prochazka, Zdenko,Slaninova, Jirina,Barth, Tomislav,Majer, Pavel,Lebl, Michal
, p. 2751 - 2760 (2007/10/02)
Four analogs of vasopressin with non-coded amino acids D-homoarginine (in position 8) and 2,6-di- or 2,4,6-trisubstituted L- or D-phenylalanine (in position 2) were synthesized using the solid phase method on p-methylbenzhydrylamine resin.All the analogs
N-terminally substituted dipeptide amides
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, (2008/06/13)
This invention encompasses compounds of the formula STR1 and the pharmaceutically acceptable acid addition salts thereof wherein R1 is lower alkoxy or --O--(CH2)n -phenyl where the phenyl may be optionally substituted with halogen, --NO2, --CN, --NH2 or lower alkyl wherein n is 1 to 4; R2 and R3 represent lower alkyl, halogen, lower alkoxy or one of R2 or R3 is hydrogen and the other is lower alkyl, lower alkoxy, or halogen; R4, R5, R7, R8, and R9 represent hydrogen or lower alkyl, R6 represents hydrogen, lower alkyl, lower alkenyl, or --(CH2)m -cycloalkyl wherein m is 1 to 4 and the cycloalkyl has 3 to 8 carbon atoms; R10 is --(CH2)p -phenyl wherein p is 1 to 4; and v represents an asymmetric carbon that may be racemic or have the D or L Configuration; w represents an asymmetric carbon when R7 and R8 are not the same that may be racemic or have the D or L configuration. This invention also encompasses compounds where R1 is hydroxy, provided at least one of R4, R5, R6 or R9 is lower alkyl. The compounds of this invention are useful analgesic agents.
