RenaSci Ltd, BioCity Nottingham, Pennyfoot Street, Nottingham NG1 1GF, UK.
Neuropharmacology. 2013 Oct;73:348-58. doi: 10.1016/j.neuropharm.2013.05.021. Epub 2013 Jun 6.
Lisdexamfetamine dimesylate, which consists of L-lysine covalently bound to D-amfetamine, is the first prodrug for treating ADHD. Its metabolic conversion to yield D-amfetamine by rate-limited, enzymatic hydrolysis is unusual because it is performed by peptidases associated with red blood cells. Other stimulants shown to be effective in managing ADHD include D-amfetamine, methylphenidate and modafinil. All have the potential for misuse or recreational abuse. The discriminative and reinforcing effects of these compounds were determined in rats using a 2-choice, D-amfetamine (0.5 mg/kg, i.p.)-cued drug-discrimination test, and by substitution for intravenous cocaine in self-administration. Lisdexamfetamine (0.5-1.5 mg/kg [D-amfetamine base], p.o.) generalised to saline when tested 15 min post-dosing, but dose-dependently generalised to d-amfetamine at 60 min. At 120 min, its D-amfetamine-like effects were substantially diminished. At 15 min, methylphenidate (3.0-10 mg/kg, p.o.) and D-amfetamine (0.1-1.5 mg/kg, p.o.) dose-dependently generalised to the intraperitoneal D-amfetamine cue. Switching to the intraperitoneal route reduced the interval required for lisdexamfetamine to be recognised as D-amfetamine-like, but did not alter its potency. Switching to intraperitoneal injection increased the potency of methylphenidate and D-amfetamine by 3.4× and 2.2×, respectively. Modafinil (50-200 mg/kg, i.p.) generalised partially, but not fully, to d-amfetamine. Methylphenidate (0.1, 0.3, 1.0 mg/kg/injection, i.v.) maintained robust self-administration at the 2 highest doses. Neither lisdexamfetamine (0.05, 0.15 or 0.5 mg/kg/injection [D-amfetamine base], i.v.) nor modafinil (0.166, 0.498 or 1.66 mg/kg/injection, i.v.) served as reinforcers. The results reveal important differences between the profiles of these stimulants. Lisdexamfetamine did not serve as a positive reinforcer in cocaine-trained rats, and although it generalised fully to D-amfetamine, its discriminative effects were markedly influenced by its unusual pharmacokinetics.
右苯丙胺硫酸盐，由赖氨酸共价键合到 D-苯丙胺组成，是治疗 ADHD 的第一种前药。它通过限速、酶促水解代谢转化为 D-苯丙胺是不寻常的，因为它是由与红细胞相关的肽酶完成的。其他被证明对 ADHD 有效的兴奋剂包括 D-苯丙胺、哌醋甲酯和莫达非尼。所有这些都有可能被滥用或娱乐性滥用。这些化合物的辨别和强化作用在大鼠中通过 2 种选择、D-苯丙胺（0.5mg/kg，ip）提示药物辨别测试和静脉注射可卡因替代自我给药来确定。Lisdexamfetamine（0.5-1.5mg/kg[D-苯丙胺碱]，po）在给药后 15 分钟测试时完全概括为盐水，但在 60 分钟时剂量依赖性地概括为 d-苯丙胺。在 120 分钟时，其 D-苯丙胺样作用大大减弱。在 15 分钟时，哌醋甲酯（3.0-10mg/kg，po）和 D-苯丙胺（0.1-1.5mg/kg，po）剂量依赖性地概括为腹腔内 D-苯丙胺线索。切换到腹腔途径减少了将 lisdexamfetamine 识别为 D-苯丙胺样所需的时间，但没有改变其效力。切换到腹腔注射分别使哌醋甲酯和 D-苯丙胺的效力增加了 3.4 倍和 2.2 倍。莫达非尼（50-200mg/kg，ip）部分概括，但不完全概括为 d-苯丙胺。哌醋甲酯（0.1、0.3、1.0mg/kg/注射，iv）在最高 2 个剂量下维持稳定的自我给药。Lisdexamfetamine（0.05、0.15 或 0.5mg/kg/注射[D-苯丙胺碱]，iv）和莫达非尼（0.166、0.498 或 1.66mg/kg/注射，iv）均不作为强化剂。结果揭示了这些兴奋剂之间的重要差异。Lisdexamfetamine 不能作为可卡因训练大鼠的正强化剂，尽管它完全概括为 D-苯丙胺，但它的辨别作用受到其不寻常的药代动力学的显著影响。
