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In order to study the structure-activity relationships of dynorphin A-(1-8) amide [Dyn(1-8)-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 mu-, delta-, and kappa-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 kappa receptor is strictly limited and that introduction of MeArg in position 7 protects the Arg6-Arg-7 bond from enzymatic degradation without potency drop and change of opioid receptor selectivity. [MeTyr1,MeArg7,D-Leu8]Dyn(1-8)-NHEt (18) [IC50 (nM) = 0.3 (GPI), 7.4 (MVD), and 2.6 (RVD); tail pinch ED50 (mg/kg) = 0.75] showed opioid activity similar to that of dynorphin A in the three bioassays and relatively high kappa-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(1-8)-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 mu and delta receptors than for the kappa receptor.

ABSTRACT-Potencyand duration of muscle relaxant activity of eperisone hydrochloride were examined after percutaneous administration in the intercollicular decerebrated rat rigidity model and compared to those of eperisone after intravenous injection. A continuous movement was loaded on the hindlimb of the rat model to maintain stable rigidity. The tonus of the hindlimb was recorded by EMG from the triceps surae and was quantified by using the public domain NIH Image program. Eperisone ointment administered percutaneously showed significant muscle relaxant activity at 8.4 cm2 (4.2 mg of eperisone)/rat. The effect was dose-dependent and lasted over 60 min. Intravenously injected eperisone showed significant activity at 1.25 mg/kg, but the decrease of tone was lost within 30 min after injection. Plasma eperisone levels were monitored in the same model, and they were well correlated to the dosage. These results suggest that per cutaneously administered eperisone is absorbed efficiently and shows potent and long-lasting muscle relax ant activity.

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