Tingyou Li, Kimitaka Shiotani, Anna Miyazaki, Yuko Tsuda, Akihiro Ambo, Yusuke Sasaki, Yunden Jinsmaa, Ewa Marczak, Sharon D. Bryant, Lawrence H. Lazarus, and Yoshio Okada
Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2) and Dmt1EM-2 (Dmt 2‘,6‘-dimethyl-l-tyrosine) analogues, containing alkylated Phe3derivatives, 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) Xaa3EM-2 analogues exhibited improved - and -opioid receptor affinities. The latter, however, were inconsequential (Ki491−3451 nM). (ii) Dmt1,Xaa3EM-2 analogues enhanced - and -opioid receptor affinities (Ki0.069−0.32 nM; Ki1.83−99.8 nM) without -opioid receptor interaction. (iii) There were elevated -bioactivity (IC500.12−14.4 nM) and abolished -agonism (IC50> 10 M in 2‘, 3‘, 4‘, 5‘, 6‘), although 4‘ and 6‘ demonstrated a potent mixed -agonism/-antagonism (for 4‘, IC500.12 and pA28.15; for 6‘, IC500.21 nM and pA29.05) and 7‘ was a dual -agonist/-agonist (IC500.17 nM; IC500.51 nM). [ABSTRACT FROM AUTHOR]