- 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
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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).
- Li, Tingyou,Shiotani, Kimitaka,Miyazaki, Anna,Tsuda, Yuko,Ambo, Akihiro,Sasaki, Yusuke,Jinsmaa, Yunden,Marczak, Ewa,Bryant, Sharon D.,Lazarus, Lawrence H.,Okada, Yoshio
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p. 2753 - 2766
(2008/02/07)
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