Ewald Amy W M, Bosch Peter J, Culverhouse Aimee, Crowley Rachel Saylor, Neuenswander Benjamin, Prisinzano Thomas E, Kivell Bronwyn M
School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand.
Department of Biology, University of Iowa, Iowa City, IA, 52242, USA.
Psychopharmacology (Berl). 2017 Aug;234(16):2499-2514. doi: 10.1007/s00213-017-4637-2. Epub 2017 May 23.
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 (FSTs), respectively.
EOM Sal B (0.1, 0.3 mg/kg, intraperitoneally (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.
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，包括镇静、烦躁不安、厌恶、焦虑和抑郁在内的副作用限制了它们的治疗开发。Salvinorin A的独特结构已被用于开发长效KOPr激动剂。
我们在临床前评估了两种新型Salvinorin A的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U50,488调节可卡因诱导行为和副作用的能力。
使用自我给药大鼠的药物寻求恢复模型评估EOM Sal B的抗可卡因特性。评估EOM Sal B和β-THP Sal B对可卡因诱导的多动、自发运动活动和蔗糖自我给药的影响。分别使用条件性位置厌恶（CPA）、高架十字迷宫（EPM）和强迫游泳试验（FST）评估EOM Sal B和β-THP Sal B的厌恶、致焦虑和抑郁样作用。
EOM Sal B（0.1、0.3毫克/千克，腹腔注射（i.p.））剂量依赖性地减弱药物寻求行为，并且EOM Sal B（0.1毫克/千克，i.p.）和β-THP Sal B（1毫克/千克，i.p.）减弱可卡因诱导的多动。EOM（0.1或0.3毫克/千克，i.p.）或β-THP Sal B（1或2毫克/千克，i.p.）对运动活动、开放臂时间（EPM）或游泳行为（FST）没有影响。然而，β-THP Sal B减少了在药物配对室中花费的时间。
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，且副作用更少。EOM Sal B对蔗糖自我给药（0.1毫克/千克）、运动、抑郁样、厌恶样或抗焦虑作用没有影响。
