Toussaint Marion, Delair Brice, Foulon Catherine, Lempereur Nadège, Vaccher Claude, Maurice Tangui, Melnyk Patricia
CNRS UMR 8161, Team 3, Lille 2 University, Lille 1 University, Pasteur Institute of Lille, 59021 Lille, France.
Eur Neuropsychopharmacol. 2009 Jul;19(7):504-15. doi: 10.1016/j.euroneuro.2009.01.008. Epub 2009 Feb 26.
Activation of the newly identified sigma(1) chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the sigma(1) protein may lead to putative potent anti-cocaine agents. Here, we synthetized substituted hydantoins with high affinity for the sigma(1) protein and evaluated their behavioral efficacy. Two pure enantiomers were designed and synthesized: tetrahydroisoquinoleine-hydantoin fused compounds 3 and 4. They increased cocaine-induced locomotor stimulation or sensitization. The most active enantiomer 4, facilitated CPP acquisition but failed to substitute for cocaine. When CPP was acquired with cocaine and then extinguished, 4 provoked reactivation of CPP. These observations showed that compound 4 shows a typical profile of sigma(1) protein activator, facilitating cocaine-induced behavioral effects. Preliminary ADME properties are in favour of an optimal therapeutic development. Such Tic-hydantoin compound may serve as a new effective agonist therapy in cocaine addiction.
新发现的σ(1)伴侣蛋白的激活参与了可卡因的精神刺激和成瘾作用的多个方面。开发选择性靶向σ(1)蛋白的配体可能会产生潜在的强效抗可卡因药物。在此，我们合成了对σ(1)蛋白具有高亲和力的取代乙内酰脲，并评估了它们的行为功效。设计并合成了两种纯对映体：四氢异喹啉-乙内酰脲融合化合物3和4。它们增强了可卡因诱导的运动刺激或敏化作用。活性最高的对映体4促进了条件性位置偏爱（CPP）的获得，但不能替代可卡因。当用可卡因获得CPP然后消除时，4引发了CPP的重新激活。这些观察结果表明，化合物4显示出典型的σ(1)蛋白激活剂特征，促进了可卡因诱导的行为效应。初步的药物代谢动力学（ADME）特性有利于最佳的治疗开发。这种噻唑-乙内酰脲化合物可能成为治疗可卡因成瘾的一种新的有效激动剂疗法。
