Synthesis and Structure-Activity Relationships of [MeTyr¹, MeArg⁷]-Dynorphin A(1-8)-OH Analogues with Substitution at Position 8

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A series of [MeTyr¹, MeArg⁷]-Dynorphin A (Dyn)(1-8)-OH analogues, modified at position 8 with various amino acids, is described. Their biological activities were determined in the three bioassays [guinea pig ileum (GPI), mouse vas deferens (MVD), and rabbit vas deferens (RVD)] and in the mouse tail-pinch test after subcutaneous administration. None of the analogues tested displayed more potent κ-opioid activity in the RVD than [MeTyr¹, MeArg⁷, D-Leu⁸]-Dyn(1-8)-NHEt (1), which is a potent analgesic peptide with similar opioid receptor selectivity to that of Dyn.However, [MeTyr¹, MeArg⁷, Melle⁸]-Dyn(1-8)-OH (11) showed about a twofold more potent analgesic effect than 1. Based on the obtained results it is conceivable that in the case of Dyn(1-8)-OH analogues both a lipophilic L-amino acid in position 8 and an unchanged 7-8 amide bond are essential to maintain potent κ-opioid activity.