The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects.
The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects.
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DOI：
10.1007/s00213-017-4637-2
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发表时间：
2017-08
影响因子：
3.4
通讯作者：
Kivell BM
中科院分区：
文献类型：
--
作者：
Ewald AWM;Bosch PJ;Culverhouse A;Crowley RS;Neuenswander B;Prisinzano TE;Kivell BM
κ-阿片受体（KOPr）激动剂具有临床前抗可卡因和镇痛作用。然而，副作用包括镇静、烦躁、厌恶、焦虑和抑郁限制了它们的治疗发展。鼠尾草素A的独特结构已用于开发长效KOPr激动剂。我们评估了鼠尾草素A的两种新型C-2类似物，乙氧基甲基醚Sal B（EOM Sal B）和β-四氢吡喃Sal B（β-THP Sal B）以及U 50，488在临床前调节可卡因诱导的行为和副作用的能力。采用自我给药大鼠的药物觅药恢复模型评价了EOM Sal B的抗可卡因特性。评价了EOM Sal B和β-THP Sal B对可卡因诱导的活动过度、自发活动和蔗糖自我给药的影响。分别采用条件性位置厌恶（CPA）、高架十字迷宫（ESTA）和强迫游泳试验（FST）评价EOM Sal B和β-THP Sal B的厌恶、焦虑和抑郁样作用。EOM Sal B（0.1、0.3 mg/kg，i.p.）剂量依赖性减弱的药物寻求和EOM Sal B（0.1 mg/kg，i. p.）和β-THP Sal B（1 mg/kg，i.p.）减轻可卡因引起的多动症在EOM（0.1或0.3 mg/kg，i. p.）中未观察到对自发活动、开臂时间（OPEN ARM TIME）或游泳行为（FST）的影响。或β-THP Sal B（1或2 mg/kg，i.p.）。然而，β-THP Sal B减少了药物配对室中的时间。EOM Sal B在减少药物寻求行为方面比Sal A和β-THP Sal B更有效，副作用更少。EOM Sal B对蔗糖自身给药（0.1 mg/kg）、运动、抑郁样、厌恶样或抗焦虑作用无影响。
Kappa-opioid receptor (KOPr) agonists have pre-clinical anti-cocaine and analgesic effects. However, side-effects including sedation, dysphoria, aversion, anxiety and depression limit their therapeutic development. The unique structure of Salvinorin A has been used to develop longer-acting KOPr agonists. We evaluate two novel C-2 analogues of Salvinorin A, ethoxymethyl ether Sal B (EOM Sal B) and β-tetrahydropyran Sal B (β-THP Sal B) alongside U50,488 for their ability to modulate cocaine-induced behaviours and side-effects, pre-clinically. Anti-cocaine properties of EOM Sal B were evaluated using the reinstatement model of drug-seeking in self-administering rats. EOM Sal B and β-THP Sal B were evaluated for effects on cocaine-induced hyperactivity, spontaneous locomotor activity and sucrose self-administration. EOM Sal B and β-THP Sal B were evaluated for aversive, anxiogenic and depressive-like effects using conditioned place aversion (CPA), elevated plus maze (EPM) and forced swim tests (FST) respectively. EOM Sal B (0.1, 0.3 mg/kg, i.p.) dose-dependently attenuated drug-seeking and EOM Sal B (0.1 mg/kg, i.p.) and β-THP Sal B (1 mg/kg, i.p.) attenuated cocaine-induced hyperactivity. No effects on locomotor activity, open arm times (EPM) or swimming behaviours (FST), were seen with EOM (0.1 or 0.3 mg/kg, i.p.) or β-THP Sal B (1 or 2 mg/kg, i.p.). However, β-THP Sal B decreased time spent in the drug-paired chamber. EOM Sal B is more potent than Sal A and β-THP Sal B in reducing drug-seeking behaviour with fewer side-effects. EOM Sal B showed no effects on sucrose self-administration (0.1 mg/kg), locomotor, depressive-like, aversive-like or anxiolytic effects.
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影响因子：
5
作者：
DiMattio KM;Ehlert FJ;Liu-Chen LY
通讯作者：
Liu-Chen LY
影响因子：
4.8
作者：
Chen, Jing;Zhang, Rumin;Bai, Bo
通讯作者：
Bai, Bo
影响因子：
3.4
作者：
Bruchas, Michael R.;Chavkin, Charles
通讯作者：
Chavkin, Charles
影响因子：
3.4
作者：
Henderson-Redmond, Angela;Czachowski, Cristine
通讯作者：
Czachowski, Cristine
影响因子：
64.8
作者：
Bohn, LM;Gainetdinov, RR;Caron, MG
通讯作者：
Caron, MG