Mulder A H, Wardeh G, Hogenboom F, Kazmierski W, Hruby V J, Schoffelmeer A N
Department of Pharmacology, Free University Medical Faculty, Amsterdam, The Netherlands.
Eur J Pharmacol. 1991 Nov 19;205(1):1-6. doi: 10.1016/0014-2999(91)90761-e.
The opioid receptor antagonist properties of four conformationally constrained cyclic octapeptide analogues of somatostatin were investigated using in vitro functional paradigms of mu-, delta- and kappa-opioid receptors in the rat brain. The analogues examined were D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), D-Tic-CTOP (TCTOP) and D-Tic-CTAP (TCTAP). Activation of mu-receptors by the enkephalin analogue Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAGO) inhibited the (electrically evoked) release of [3H]noradrenaline (NA) from superfused cortical slices and this inhibitory effect was antagonized in a competitive fashion by all of the octapeptides tested (pA2 values: CTOP and CTAP 7.9-8.0, TCTOP and TCTAP 8.7-8.8). Selective activation of kappa-opioid receptors by the cyclohexylbenzeneaceamide U69593 (0.02 microM) inhibited (by 40-45%) the release of [3H]dopamine (DA) from striatal slices, whereas selective activation of delta-opioid receptors by [D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6 (DSTBULET; 0.1 microM) caused an inhibition (by 38-46%) of striatal [14C]acetylcholine (ACh) release. However, these inhibitory effects were not affected by any of the octapeptides in concentrations that caused full antagonism of the inhibitory effect (55-65%) of 0.1 microM DAGO on cortical [3H]NA release. Thus, the cyclic octapeptide somatostatin analogues CTOP, CTAP, TCTOP and TCTAP are potent and highly selective antagonists at the mu-opioid receptors mediating presynaptic inhibition of NA release in the brain. The mu-receptor affinity of the most potent of these antagonists, TCTOP and TCTAP, appears to be similar to that of naloxone but these antagonists have a much greater selectivity than the latter.
利用大鼠脑中μ-、δ-和κ-阿片受体的体外功能范式，研究了四种构象受限的生长抑素环八肽类似物的阿片受体拮抗剂特性。所检测的类似物为D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2（CTOP）、D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2（CTAP）、D-Tic-CTOP（TCTOP）和D-Tic-CTAP（TCTAP）。脑啡肽类似物Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol（DAGO）对μ-受体的激活抑制了[3H]去甲肾上腺素（NA）从灌流皮质切片中的（电诱发）释放，而所有测试的八肽均以竞争性方式拮抗这种抑制作用（pA2值：CTOP和CTAP为7.9 - 8.0，TCTOP和TCTAP为8.7 - 8.8）。环己基苯乙酰胺U69593（0.02 microM）对κ-阿片受体的选择性激活抑制了[3H]多巴胺（DA）从纹状体切片中的释放（抑制40 - 45%），而[D-Ser2(O-t-丁基),Leu5]脑啡肽-Thr6（DSTBULET；0.1 microM）对δ-阿片受体的选择性激活导致纹状体[14C]乙酰胆碱（ACh）释放受到抑制（抑制38 - 46%）。然而，这些抑制作用不受任何八肽的影响，这些八肽的浓度可完全拮抗0.1 microM DAGO对皮质[3H]NA释放的抑制作用（55 - 65%）。因此，环八肽生长抑素类似物CTOP、CTAP、TCTOP和TCTAP是介导脑中NA释放突触前抑制的μ-阿片受体的强效且高度选择性拮抗剂。这些拮抗剂中最有效的TCTOP和TCTAP对μ-受体的亲和力似乎与纳洛酮相似，但这些拮抗剂的选择性比纳洛酮高得多。
