SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF DYNORPHIN-A-(1-8) AMIDE ANALOGS

In order to study the structure-activity relationships of dynorphin A-(l-8) amide [Dyn(l-8)-NH2], 20 analogues were synthesized by the solution method. 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 intravenous administration. Some analogues that showed interesting activity in the bioassays and/or in the analgesic tests were further characterized in µ-, δ and ϰ-representative binding assays. The obtained data indicate that modification of the enkephalin segment to give metabolically stable analogues with high affinity and selectivity for the ϰ receptor is strictly limited and that introduction of MeArg in position 7 protects the Arg6-Arg7bond from enzymatic degradation without potency drop and change of opioid receptor selectivity. [MeTyr7,MeArg7,d-Leu8]Dyn(l-8)-NHEt (18) [ICM (nM) = 0.3 (GPI), 7.4 (MVD), and 2.6 (RVD); tail pinch ED.50(mg/kg) = 0.75] showed opioid activity similar to that of dynorphin A in the three bioassays and relatively high ϰ-receptor selectivity in the binding assays and produced a 2.5-fold more potent analgesic effect than morphine. [D-Cys2-Cys5,MeArg7,d-Leu8]Dyn(l-8)-NHEt (20) showed a 40-60-fold more potent opioid activity than 18 in the three bioassays and produced a 3.4-fold more potent analgesic effect than 18. In the binding assays, however, 20 showed higher affinity for µ and δ receptors than for the ϰ receptor. © 1990, American Chemical Society. All rights reserved.