Horan P J, Wild K D, Kazmierski W M, Ferguson R, Hruby V J, Weber S J, Davis T P, Fang L, Knapp R J, Yamamura H I
Department of Pharmacology, University of Arizona, Tucson 85724.
Eur J Pharmacol. 1993 Mar 16;233(1):53-62. doi: 10.1016/0014-2999(93)90348-l.
This study tested the hypothesis that compounds which may bind simultaneously to delta and mu receptors may be more potent antinociceptive agents than would be predicted from their binding affinities at individual mu and delta opioid receptors. D-Tca-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 ([D-Tca1]CTAP) (where D-Tca is a cyclic D-tryptophan analogue) was synthesized and evaluated in radioligand competition assays, opioid bioassays, and in an antinociceptive assay (the tail-flick test in mice). Additionally, the metabolic stability of [D-Tca1]CTAP was evaluated in striatal and cerebellar tissue slices. In rat brain in vitro, [D-Tca1]CTAP competed weakly for sites labelled by [3H]D-Phe-Cys-Tyr-D-Trp-Om-Thr-Pen-Thr-NH2 ([3H]CTOP) (mu-ligand), and [3H][D-Pen2,pCl-Phe4,D-Pen5]enkephalin (delta-ligand); [D-Pen2,D-Pen5]enkephalin (DPDPE) (delta-agonist) was 6.5-fold less and 230-fold more potent, respectively, against these ligands. Additionally, in mouse isolated vas deferens and guinea pig isolated ileum smooth muscle preparations, [D-Tca1]CTAP proved to be weak as either a delta (IC50 of approximately 2 microM) or mu (IC50 > 8 microM) receptor agonist. Surprisingly, however, i.c.v. [D-Tca1]CTAP produced antinociception with potency similar to DPDPE. The antinociceptive actions of [D-Tca1]CTAP were apparently not due to a metabolite or the release of endogenous opioids, as this compound proved stable in both striatal and cerebellar tissue slices and its antinociceptive actions were not enhanced by the 'enkephalinase' inhibitor thiorphan. The suggestion that [D-Tca1]CTAP might be acting by binding simultaneously to mu and delta receptors to produce its antinociceptive effect is supported by the demonstrated antagonism resulting from mu receptor blockade with either beta-funaltrexamine (beta-FNA) or naloxonazine, or by delta receptor blockade by ICI 174,864 ([N,N-diallyl-Tyr1,Aib2,3,Leu5] enkephalin). Furthermore, the antinociceptive properties of [D-Tca1]CTAP were antagonized by (naltrindole-5'-isothiocyanate) (5'-NTII), an antagonist at the delta 2 opioid receptor subtype, but not by the delta 1 antagonist [D-Ala2,D-Leu5,Cys6]enkephalin (DALCE). Additionally, no antagonism was produced by nor-binaltorphimine (nor-BNI), a kappa antagonist. From these data, [D-Tca1]CTAP appears to bind to mu, and 5'-NTII-sensitive delta 2, opioid receptors, and may represent the first of a class of compounds which may act at an opioid receptor complex via 'self-potentiation'.
本研究检验了这样一个假设：能够同时与δ和μ受体结合的化合物可能比根据其对单个μ和δ阿片受体的结合亲和力所预测的更具强效镇痛作用。合成了D-Tca-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2（[D-Tca1]CTAP）（其中D-Tca是一种环状D-色氨酸类似物），并在放射性配体竞争试验、阿片生物测定以及镇痛试验（小鼠甩尾试验）中对其进行了评估。此外，还在纹状体和小脑组织切片中评估了[D-Tca1]CTAP的代谢稳定性。在大鼠脑体外实验中，[D-Tca1]CTAP对由[3H]D-Phe-Cys-Tyr-D-Trp-Om-Thr-Pen-Thr-NH2（[3H]CTOP）（μ配体）和[3H][D-Pen2,pCl-Phe4,D-Pen5]脑啡肽（δ配体）标记的位点竞争较弱；[D-Pen2,D-Pen5]脑啡肽（DPDPE）（δ激动剂）对这些配体的效力分别低6.5倍和高230倍。此外，在小鼠离体输精管和豚鼠离体回肠平滑肌制剂中，[D-Tca1]CTAP作为δ（IC50约为2μM）或μ（IC50>8μM）受体激动剂均表现较弱。然而，令人惊讶的是，脑室内注射[D-Tca1]CTAP产生的镇痛作用与DPDPE相似。[D-Tca1]CTAP的镇痛作用显然不是由于代谢产物或内源性阿片类物质的释放，因为该化合物在纹状体和小脑组织切片中均稳定，且其镇痛作用不会因“脑啡肽酶”抑制剂硫喷妥而增强。β-芬太尼（β-FNA）或纳洛酮嗪对μ受体的阻断，或ICI 174,864（[N,N-二烯丙基-Tyr1,Aib2,3,Leu5]脑啡肽）对δ受体的阻断所产生的拮抗作用，支持了[D-Tca1]CTAP可能通过同时结合μ和δ受体来产生其镇痛作用的观点。此外，[D-Tca1]CTAP的镇痛特性被δ2阿片受体亚型拮抗剂（纳曲吲哚-5'-异硫氰酸酯）（5'-NTII）拮抗，但不被δ1拮抗剂[D-Ala2,D-Leu5,Cys6]脑啡肽（DALCE）拮抗。此外，κ拮抗剂去甲二丙诺啡（nor-BNI）未产生拮抗作用。根据这些数据，[D-Tca1]CTAP似乎与μ以及对5'-NTII敏感的δ2阿片受体结合，并且可能代表了一类可通过“自我增强”作用于阿片受体复合物的化合物中的首个成员。
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