Medication development of agonist-type treatment agents for stimulant addiction

兴奋剂成瘾激动剂型治疗剂的药物开发

• 批准号: 10004985
• 负责人: Michael Baumann
• 金额: $ 37.41万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10004985
• 关键词: Adrenergic Receptor; Advocate; Affinity; Agonist; Amphetamines; Binding; Binding Sites; Brain; Bupropion; Carrier Proteins; Cell membrane; Clinical Trials; Cocaine; Data; Designer Drugs; Development; Dopamine; Exhibits; FDA approved; Hybrids; Journals; Ligands; MEN1 gene; Mental disorders; Methadone; Methamphetamine; Neurons; Nicotine; Norepinephrine; Opioid; Paper; Parents; Peer Review; Pharmaceutical Preparations; Pharmacology Study; Pharmacotherapy; Psychostimulant dependence; Public Health; Publishing; Recreational Drugs; Ritalin; Serotonin; Serotonin Receptor 5-HT2B; Structure; Substance Use Disorder; Testing; United States; addiction; alcoholism therapy; analog; cathinone; dopamine transporter; drug development; drug market; drug seeking behavior; ecstasy; effective therapy; member; monoamine; noradrenaline transporter; novel; preclinical study; psychostimulant; receptor; serotonin transporter; stimulant abuse; varenicline

Summary- Significant progress was made on this project, which involves the development of medications for psychiatric diseases, especially substance use disorders. Five relevant papers were published in peer-reviewed journals. In a key article, we show that phenyl ring-substitution of aminoindan analogs increases the potency at 5-HT transporters (SERT) relative to dopamine transporters (DAT) and norepinephrine transporters (NET). Aminoindans with greater activity at SERT might have utility as medications with reduced abuse potential. Over the last decade, many psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Many of these agents are similar to widely prescribed medications like methylphenidate and bupropion. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs, whereas others such as 5-methoxy-2-aminoindan (5-MeO-AI or MEAI) show promise as a treatments for alcoholism. Here, we tested 2-AI and its ring-substituted derivatives 5-MeO-AI, 5-methoxy-6-methyl-2-aminoindan (MMAI), and 5,6-methylenedioxy-2-aminoindan (MDAI) for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We also compared the binding affinities of the aminoindans at 29 receptor and transporter binding sites. 2-AI was a selective substrate for NET and DAT. Ring substitution increased potency at SERT while reducing potency at DAT and NET. MDAI was moderately selective for SERT and NET, with tenfold weaker effects on DAT. 5-MeO-AI exhibited some selectivity for SERT, having sixfold lower potency at NET and 20-fold lower potency at DAT. MMAI was highly selective for SERT, with 100-fold lower potency at NET and DAT. The aminoindans had relatively high affinity for 2-adrenoceptor subtypes. 2-AI had particularly high affinity for 2C receptors (Ki=41 nM) and slightly lower affinity for the 2A (Ki=134 nM) and 2B (Ki=211 nM) subtypes. 5-MeO-AI and MMAI also had moderate affinity for the 5-HT2B receptor. 2-AI is predicted to have (+)-amphetamine-like effects and abuse potential whereas the ring-substituted derivatives may produce 3,4-methylenedioxymethamphetamine (MDMA)-like effects but with less abuse liability.

摘要--该项目取得了重大进展，包括开发治疗精神疾病，特别是药物使用障碍的药物。五篇相关论文发表在同行评议的期刊上。在一篇关键文章中，我们证明了氨基吲哚类似物的苯环取代增加了相对于多巴胺转运体(DAT)和去甲肾上腺素转运体(NET)的5-羟色胺转运体(SERT)的效力。氨基吲哚类药物在SERT中具有更大的活性，作为减少滥用潜力的药物可能有实用价值。 在过去的十年里，娱乐毒品市场上出现了许多精神刺激剂类似物，其中大多数是苯丙胺或卡西酮的衍生物。其中许多药物类似于广泛使用的处方药物，如哌醋甲酯和安非他酮。另一类设计药物来自2-氨基吲哚结构模板。这一类的几个成员，包括母体化合物2-氨基吲哚(2-AI)，已经作为特制药物出售，而其他成员，如5-甲氧基-2-氨基吲哚(5-MeO-AI或MEAI)，显示出作为治疗酒精中毒的希望。在这里，我们测试了2-AI及其环取代衍生物5-MeO-AI、5-甲氧基-6-甲基-2-氨基吲哚(MMAI)和5，6-亚甲二氧基-2-氨基吲哚(MDAI)与质膜单胺转运体多巴胺(DAT)、去甲肾上腺素(NET)和5-羟色胺(SERT)的相互作用能力。我们还比较了29个受体和转运体结合位点上氨基吲哚的结合亲和力。2-AI是NET和DAT的选择性底物。环替代提高了SERT的效力，而降低了DAT和NET的效力。MDAI对SERT和NET具有中等选择性，对DAT的选择性较弱10倍。5-MeO-AI对SERT有一定的选择性，净效价低6倍，DAT效价低20倍。MMAI对SERT具有很高的选择性，在Net和DAT上的效力降低了100倍。氨基吲哚对2-肾上腺素能受体亚型有较高的亲和力。2-AI对2C受体的亲和力特别高(Ki=41 nM)，而对2A(Ki=134 nM)和2B(Ki=211 nM)亚型的亲和力稍低。5-MeO-AI和MMAI对5-HT2B受体也有中等亲和力。2-AI被预测具有(+)-苯丙胺样作用和滥用潜力，而环取代的衍生物可能产生3，4-亚甲基二氧甲基苯丙胺(MDMA)样作用，但滥用可能性较小。