Shimoyama M, Shimoyama N, Zhao G M, Schiller P W, Szeto H H
Department of Physiology, Chiba University School of Medicine, Chuo-ku, Chiba-shi, Chiba-ken, Japan.
J Pharmacol Exp Ther. 2001 Apr;297(1):364-71.
DALDA (H-Tyr-D-Arg-Phe-Lys-NH(2)) and [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH(2)) (Dmt = 2',6'-dimethyltyrosine) are potent and highly selective mu-opioid agonists (K(i)(delta)/K(i)(mu) > 10,000 and K(i)(kappa)/K(i)(mu) > 100). Both peptides carry a 3+ charge at physiological pH. Their antinociceptive and respiratory effects were compared with morphine (MOR) after intrathecal administration in rats. Both DALDA and [Dmt1]DALDA produced dose-dependent and naloxone-reversible antinociceptive effects with relative potencies of 14 and 3000x that of MOR. The antinociceptive potency of [Dmt1]DALDA far exceeded its affinity and potency at the mu-opioid receptor and may be explained by its ability to inhibit norepinephrine (NE) uptake in spinal cord synaptosomes. The antinociceptive response to [Dmt1]DALDA was significantly attenuated by the alpha(2)-adrenergic antagonist yohimbine. Thus, [Dmt1]DALDA may be regarded as a drug with dual actions, and its antinociceptive potency is better described by both its affinity and potency at mu-opioid receptors, and its potency at inhibiting NE uptake. The analgesic duration of an equipotent dose of MOR, DALDA, and [Dmt1]DALDA was 3, 7, and 13 h, respectively, and the long duration may be due to the hydrophilic nature of these peptide analogs. Respiratory effects were determined using whole body plethysmography at 3 and 30x the antinociceptive ED(50). A significant depression in minute ventilation was observed with the higher dose of morphine and both doses of DALDA, but not with either dose of [Dmt1]DALDA. Because of its high antinociceptive potency, long duration of action, and low propensity to induce respiratory depression, [Dmt1]DALDA is of interest as a drug candidate for intrathecal analgesia.
DALDA（H-Tyr-D-Arg-Phe-Lys-NH₂）和[Dmt(1)]DALDA（H-Dmt-D-Arg-Phe-Lys-NH₂）（Dmt = 2',6'-二甲基酪氨酸）是强效且高度选择性的μ阿片受体激动剂（K(i)(δ)/K(i)(μ) > 10,000且K(i)(κ)/K(i)(μ) > 100）。在生理pH条件下，这两种肽均带3个正电荷。在大鼠鞘内给药后，将它们的抗伤害感受和呼吸作用与吗啡（MOR）进行了比较。DALDA和[Dmt1]DALDA均产生剂量依赖性且纳洛酮可逆转的抗伤害感受作用，相对效价分别为MOR的14倍和3000倍。[Dmt1]DALDA的抗伤害感受效价远远超过其对μ阿片受体的亲和力和效价，这可能与其抑制脊髓突触体中去甲肾上腺素（NE）摄取的能力有关。α₂肾上腺素能拮抗剂育亨宾可显著减弱对[Dmt1]DALDA的抗伤害感受反应。因此，[Dmt1]DALDA可被视为具有双重作用的药物，其抗伤害感受效价可以通过其对μ阿片受体的亲和力和效价以及抑制NE摄取的效价来更好地描述。等效剂量的MOR, DALDA和[Dmt1]DALDA的镇痛持续时间分别为3小时、7小时和13小时，而较长的持续时间可能归因于这些肽类似物的亲水性。使用全身体积描记法在抗伤害感受ED(50)的3倍和30倍剂量下测定呼吸作用。较高剂量的吗啡以及两种剂量的DALDA均观察到分钟通气量显著降低，但两种剂量的[Dmt1]DALDA均未观察到这种情况。由于其高抗伤害感受效价、长作用持续时间以及低诱发呼吸抑制的倾向，[Dmt1]DALDA作为鞘内镇痛的候选药物具有研究价值。
