The effects of herkinorin, the first mu-selective ligand from a salvinorin A-derived scaffold, in a neuroendocrine biomarker assay in nonhuman primates.
The effects of herkinorin, the first mu-selective ligand from a salvinorin A-derived scaffold, in a neuroendocrine biomarker assay in nonhuman primates.
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DOI：
10.1124/jpet.108.140079
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发表时间：
2008-10
影响因子：
3.5
通讯作者：
Kreek, Mary Jeanne
中科院分区：
文献类型：
--
作者：
Butelman, Eduardo R.;Rus, Szymon;Simpson, Denise S.;Wolf, Angela;Prisinzano, Thomas E.;Kreek, Mary Jeanne
Herkinorin 是来自 salvinorin A 二萜类支架的第一个 μ-阿片受体 (MOP-r) 选择性配体。 Herkinorin 具有相对 μ>κ>δ 结合选择性，并且在体外可充当 μ- 和 κ- 受体的激动剂。这些研究首次利用催乳素释放对海激肽在非人类灵长类动物中的作用进行了体内评估，催乳素释放是一种神经内分泌生物标志物测定，对 μ- 和 κ- 激动剂以及穿过血脑屏障能力有限的化合物都有反应。在累积剂量研究（0.01-0.32 mg/kg，静脉注射）中，海激肽对性腺完整的男性 (n=4) 仅产生很小的影响，但对女性 (n=4) 产生更强的影响。赫基诺林 (0.32 mg/kg) 的时程研究证实了这种对女性的有效性更高，并显示静脉注射后起效快（例如 5-15 分钟）。不同剂量的纳美芬（0.01 和 0.1 mg/kg）的拮抗实验导致雌性中赫基诺林效应的剂量依赖性和完全预防。这与赫基诺林的主要 μ 激动剂作用一致，可能部分由 κ 激动剂作用贡献。外周选择性拮抗剂季纳曲酮（1 mg/kg，皮下注射）导致女性中赫基诺林（0.32 mg/kg）的峰值效应降低约 70%，表明赫基诺林的这种作用主要是在血脑屏障之外介导的。
Herkinorin is the first μ-opioid receptor (MOP-r) selective ligand from the salvinorin A diterpenoid scaffold. Herkinorin has relative μ>κ>δ binding selectivity, and can act as an agonist at both μ- and κ-receptors, in vitro. These studies were the first in vivo evaluation of herkinorin's effects in non-human primates, using prolactin release, a neuroendocrine biomarker assay that is responsive to both μ- and κ- agonists, as well as to compounds with limited ability to cross the blood-brain barrier. In cumulative dosing studies (0.01-0.32 mg/kg, i.v.), herkinorin produced only small effects in gonadally intact males (n=4), but a more robust effect in females (n=4). Timecourse studies with herkinorin (0.32 mg/kg) confirmed this greater effectiveness in females, and revealed a fast onset after i.v., administration (e.g., by 5-15 min). Antagonism experiments with different doses of nalmefene (0.01 and 0.1 mg/kg) caused dose-dependent and complete prevention of herkinorin's effect in females. This is consistent with a principal μ-agonist effect of herkinorin, with likely partial contribution by κ-agonist effects. The peripherally selective antagonist quaternary naltrexone (1 mg/kg, s.c.) caused approximately 70% reduction in the peak effect of herkinorin (0.32 mg/kg) in females, indicating that this effect of herkinorin is prominently mediated outside the blood-brain barrier.
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影响因子：
3.7
作者：
HOEHE, M;DUKA, T;DOENICKE, A
通讯作者：
DOENICKE, A
影响因子：
7.3
作者：
Harding, WW;Tidgewell, K;Prisinzano, TE
通讯作者：
Prisinzano, TE
影响因子：
6.1
作者：
VALENTINO, RJ;KATZ, JL;WOODS, JH
通讯作者：
WOODS, JH
影响因子：
2.3
作者：
Xu, Heng;Partilla, John S.;Rothman, Richard B.
通讯作者：
Rothman, Richard B.
DOI：
10.1124/jpet.103.050682
发表时间：
2003-08-01
影响因子：
3.5
作者：
Bart, G;Borg, L;Kreek, MJ
通讯作者：
Kreek, MJ