Cocaine-like discriminative stimulus effects of alpha-pyrrolidinovalerophenone, methcathinone and their 3,4-methylenedioxy or 4-methyl analogs in rhesus monkeys.
Cocaine-like discriminative stimulus effects of alpha-pyrrolidinovalerophenone, methcathinone and their 3,4-methylenedioxy or 4-methyl analogs in rhesus monkeys.
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DOI：
10.1111/adb.12399
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发表时间：
2017-09
影响因子：
3.4
通讯作者：
Banks ML
中科院分区：
文献类型：
--
作者：
Smith DA;Negus SS;Poklis JL;Blough BE;Banks ML
合成卡西酮是β-酮安非他明类似物，其已作为一种异质类别的滥用化合物出现，其用作单胺转运蛋白底物或抑制剂。临床前药物鉴别程序可用于询问滥用相关药物效应的构效关系（SAR）;然而，缺乏具有不同作用机制的合成卡西酮之间的体内SAR比较。本研究的目的是确定是否可卡因样的歧视性刺激单胺转运蛋白抑制剂α-吡咯烷戊酮（α-PVP）和单胺转运蛋白底物甲卡西酮的影响是不同的敏感性3，4-亚甲二氧基和4-甲基取代。训练雄性恒河猴（n=4）在两个关键的食物强化辨别程序中辨别肌内可卡因（0.32 mg/kg）和盐水。测定了（±）-α-PVP、（±）-甲卡西酮及其3，4-亚甲二氧基或4-甲基类似物的可卡因样辨别刺激效应的效力和时程。α-PVP和甲卡西酮产生剂量和时间依赖性可卡因样作用。将3，4-亚甲二氧基添加到α-PVP（MDPV）或甲卡西酮（MDMC;甲酮）中不会改变产生可卡因样作用的效力或功效，但确实延长了时程。将4-甲基添加到α-PVP（4 MPVP;吡咯戊酮）中不会改变产生可卡因样作用的效力或功效，但确实延长了时间进程。相比之下，向甲卡西酮（4 MMC;甲氧麻黄酮）中添加4-甲基部分显著减弱了产生可卡因样作用的功效。总体而言，这些结果表明可卡因样的单胺转运蛋白抑制剂和底物合成卡西酮类似物的区别刺激作用的不同结构要求。鉴于4 MMC比MDMC更疏水，这些结果表明疏水性可能是限制单胺转运蛋白底物滥用相关行为效应的重要决定因素。
Synthetic cathinones are beta-ketone amphetamine analogs that have emerged as a heterogeneous class of abused compounds that function as either monoamine transporter substrates or inhibitors. Preclinical drug discrimination procedures are useful for interrogating structure-activity relationships (SAR) of abuse-related drug effects; however, in vivo SAR comparisons between synthetic cathinones with different mechanisms of action are lacking. The aim of the present study was to determine whether the cocaine-like discriminative stimulus effects of the monoamine transporter inhibitor alpha-pyrrolidinovalerophenone (alpha-PVP) and the monoamine transporter substrate methcathinone were differentially sensitive to 3,4-methylenedioxy and 4-methyl substitutions. Male rhesus monkeys (n=4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Potency and timecourse of cocaine-like discriminative stimulus effects were determined for (±)-alpha-PVP, (±)-methcathinone, and their 3,4-methylenedioxy or 4-methyl analogs. Alpha-PVP and methcathinone produced dose- and time-dependent cocaine-like effects. A 3,4-methylenedioxy addition to either alpha-PVP (MDPV) or methcathinone (MDMC; methylone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. A 4-methyl addition to alpha-PVP (4MPVP; pyrovalerone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. In contrast, addition of a 4-methyl moiety to methcathinone (4MMC; mephedrone) significantly attenuated efficacy to produce cocaine-like effects. Overall, these results suggest different structural requirements for cocaine-like discriminative stimulus effects of monoamine transporter inhibitor and substrate synthetic cathinone analogs. Given that 4MMC is more hydrophobic than MDMC, these results suggest hydrophobicity may be an important determinant for limiting monoamine transporter substrate abuse-related behavioral effects.
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影响因子：
3.4
作者：
Gatch, Michael B.;Rutledge, Margaret A.;Forster, Michael J.
通讯作者：
Forster, Michael J.
影响因子：
7.3
作者：
Bauer, C. T.;Banks, M. L.;Negus, S. S.
通讯作者：
Negus, S. S.
DOI：
10.1124/jpet.110.176271
发表时间：
2011-04-01
影响因子：
3.5
作者：
Baumann, Michael H.;Clark, Robert D.;Rothman, Richard B.
通讯作者：
Rothman, Richard B.
影响因子：
4.2
作者：
Carhart-Harris, R. L.;King, L. A.;Nutt, D. J.
通讯作者：
Nutt, D. J.
影响因子：
3.8
作者：
Lai, Foon Yin;Thai, Phong K.;Mueller, Jochen F.
通讯作者：
Mueller, Jochen F.