CYCLIC SOMATOSTATIN ANALOGS AS POTENT ANTAGONISTS AT MU-OPIOID, BUT NOT DELTA-OPIOID AND KAPPA-OPIOID RECEPTORS MEDIATING PRESYNAPTIC INHIBITION OF NEUROTRANSMITTER RELEASE IN THE BRAIN
CYCLIC SOMATOSTATIN ANALOGS AS POTENT ANTAGONISTS AT MU-OPIOID, BUT NOT DELTA-OPIOID AND KAPPA-OPIOID RECEPTORS MEDIATING PRESYNAPTIC INHIBITION OF NEUROTRANSMITTER RELEASE IN THE BRAIN
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DOI：
10.1016/0014-2999(91)90761-e
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发表时间：
1991-11-19
影响因子：
5
通讯作者：
SCHOFFELMEER, ANM
中科院分区：
文献类型：
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作者：
MULDER, AH;WARDEH, G;SCHOFFELMEER, ANM
使用大鼠脑中 mu-、delta-和 kappa-阿片受体的体外功能范例研究了生长抑素的四种构象限制的环状八肽类似物的阿片受体拮抗剂特性。 检查的类似物是 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) 激活 mu 受体可抑制灌注皮质切片中 [H-3] 去甲肾上腺素 (NA) 的（电诱发）释放，并且所有测试的八肽以竞争性方式拮抗这种抑制作用（pA2 值：CTOP 和 CTAP 7.9-8.0， TCTOP 和 TCTAP 8.7-8.8）。 环己基苯乙酰胺 U69593 (0.02-mu-M) 选择性激活 κ-阿片受体可抑制 (40-45%) 纹状体切片 [H-3] 多巴胺 (DA) 的释放，而 [D-Ser2(O-t-丁基),Leu5]enkephalyl-Thr6 选择性激活 δ-阿片受体（DSTBULET；0.1-mu-M）引起纹状体 [C-14] 乙酰胆碱 (ACh) 释放的抑制（38-46%）。 然而，这些抑制作用不受任何八肽浓度的影响，该八肽引起完全拮抗0.1-mu-M DAGO对皮质[H-3]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是介导大脑中NA释放的突触前抑制的μ阿片受体的有效且高度选择性的拮抗剂。 这些拮抗剂中最有效的 TCTOP 和 TCTAP 的 mu 受体亲和力似乎与纳洛酮相似，但这些拮抗剂的选择性比后者高得多。
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 [H-3]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 cyclohexylbenzeneacetamide U69593 (0.02-mu-M) inhibited (by 40-45%) the release of [H-3]dopamine (DA) from striatal slices, whereas selective activation of delta-opioid receptors by [D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6 (DSTBULET; 0.1-mu-M) caused an inhibition (by 38-46%) of striatal [C-14]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-mu-M DAGO on cortical [H-3]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.