332186-76-2Relevant articles and documents
Stereospecific synthesis of (2S)-2-methyl-3-(2′,6′-dimethyl-4′-hydroxyphenyl)-propionic acid (Mdp) and its incorporation into an opioid peptide
Lu, Yixin,Weltrowska, Grazyna,Lemieux, Carole,Chung, Nga N.,Schiller, Peter W.
, p. 323 - 325 (2007/10/03)
To examine the effect of replacing the N-terminal amino group in opioid peptides with a methyl group on biological activity, a stereospecific synthesis of the tyrosine analogue (2S)-2-methyl-3-(2′,6′-dimethyl-4′-hydroxyphenyl)-propionic acid (Mdp) was performed. The enkephalin analogue (2S)-Mdp-D-Ala-Gly-Phe-Leu-NH2 turned out to be a quite potent δ opioid antagonist and a somewhat less potent μ antagonist, indicating that a positively charged N-terminal amino group is not a conditio sine qua non for the binding of opioid peptides to δ and μ receptors but may be required for signal transduction.
Stereospecific syntheses of 2-alkyl and 2-phenyl substituted 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acids
Lu,Schiller
, p. 1639 - 1644 (2007/10/03)
Stereospecific syntheses of 2-methyl-, 2-ethyl-, 2-cyclohexyland 2-phenyl- substituted 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acids were developed. The key steps for the formation of the stereogenic centers involved the utilization of Evans' 4-benzyl-2-oxazolidinone chiral auxiliary. These compounds were designed to replace the N-terminal tyrosine residue in opioid peptides.
Evolution of the Dmt-Tic pharmacophore: N-terminal methylated derivatives with extraordinary δ opioid antagonist activity
Salvadori, Severe,Balboni, Gianfranco,Guerrini, Remo,Tomatis, Roberto,Bianchi, Clementina,Bryant, Sharon D.,Cooper, Peter S.,Lazarus, Lawrence H.
, p. 3100 - 3108 (2007/10/03)
The δ opioid antagonist H-Dmt-Tic-OH (2',6'-dimethyl-L-tyrosyl-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid) exhibits extraordinary δ receptor binding characteristics [K(i)(δ) = 0.022 nM; K(i)(μ)/K(i)(δ) = 150 000] and δ antagonism (pA2 = 8.2; Ke = 5.7 nM). A change in chirality of Dmt at Cα (1, 2, 6, 8, 10, 13) curtailed δ receptor parameters, while replacement of its α-amino function by a methyl group (3) led to inactivity; Tyr-Tic analogues 4 and 11 weakly interacted with δ receptors. N-Alkylation of H- Dmt-Tic-OH and H-Dmt-Tic-Ala-OH with methyl groups produced potent δ-opioid ligands with high δ receptor binding capabilities and enhanced δ antagonism: (i) N-Me-Dmt-Tic-OH 5 had high δ opioid binding (K(i)(δ) = 0.2 nM), elevated δ antagonism on mouse vas deferens (MVD) (pA2 = 8.5; K(e) = 2.8 nM), and nondetectable μ activity with guinea pig ileum (GPI). (ii) N,N- Me2-Dmt-Tic-OH (12) was equally efficacious in δ receptor binding (K(i)(δ) = 0.12 nM; K(i)(μ)/K(i)(δ) = 20 000), but δ antagonism rose considerably (pA2 = 9.4; K(e) = 0.28 nM) with weak μ antagonism (pA2 = 5.8; K(e) = 1.58 μM; GPI/MVD = 1:5640). N-Me-(9) and N,N-Me2-Dmt-Tic-Ala-OH (15) also augmented δ opioid receptor binding, such that 15 demonstrated high affinity (K(i)(δ) = 0.0755 nM) and selectivity (K(i)(μ)/K(i)(δ) = 20 132) with exceptional antagonist activity on MVD (pA2 = 9.6; K(e) = 0.22 nM) and weak antagonism on GPI (pA2 = 5.8; K(e) = 1.58 μM; GPI/MVD = 1:7180). Although the amidated dimethylated dipeptide analogue 14 had high K(i)(δ) (0.31 nM) and excellent antagonist activity (pA2 = 9.9; K(e) = 0.12 nM), the increased activity toward μ receptors in the absence of a free acid function at the C- terminus revealed modest δ selectivity (K(i)(μ)/KK(i)(δ) = 1 655) and somewhat comparable bioactivity (GPI/MVD = 4500). Thus, the data demonstrate that N,N-(Me)2-Dmt-Tic-OH (12) and N,NMe2-Dmt-Tic-Ala-OH (15) retained high δ receptor affinities and δ selectivities and acquired enhanced potency in pharmacological bioassays on MVD greater than that of other peptide or non- peptide δ antagonists.
