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: 8336471
• 负责人: Richard Rothman
• 金额: $ 55.27万
• 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/8336471
• 关键词: Address; Advocate; Agonist; Alcohols; Amphetamines; Animal Model; Benserazide; Biogenic Amine Neurotransmitters; Biogenic Amines; Brain; Central Nervous System Stimulants; Clinical; Clinical Trials; Cocaine; Collaborations; Conscious; Data; Detection; Development; Dialysis procedure; Dopamine; Dose; Drug Resistant Tuberculosis; Extramural Activities; FDA approved; Funding; HIV-1; Heart Valve Diseases; Hepatitis B; Hepatitis C; High Pressure Liquid Chromatography; Housing; Human; Hyperactive behavior; In Vitro; Ligands; Locomotion; Measures; Mediating; Methamphetamine; Microdialysis; Movement; National Institute of Drug Abuse; Nicotine Dependence; Nucleus Accumbens; Opiate Addiction; Paper; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenmetrazine; Process; Property; Psychostimulant dependence; Public Health; Publishing; Rattus; Relapse; Reporting; Sampling; Self Administration; Serotonin; Serotonin Receptor 5-HT2B; Structure; Synapses; Testing; Time; Tryptophan; United States; analog; base; decarboxylase inhibitor; dopamine transporter; drug seeking behavior; effective therapy; extracellular; in vitro Assay; in vivo; intravenous injection; male; monoamine; neurochemistry; preclinical study; prevent; stereotypy; stimulant abuse; transmission process

Significant progress was made during this reporting period. In collaboration with Dr. Blough, we continued to evaluate a large number of newly synthesized compounds using in vitro assays. The current focus is on DA/5-HT releasers based on the phenmetrazine structure, since these compounds have minimal activity at the 5-HT2B receptor. A key aspect of this project is to avoid making compounds that activate 5-HT2B receptors, since this property is associated with the development of cardiac valve disease in humans. We published In collaboration with Dr. Ananthan, who received extramural NIDA funding for further identification of dopamine transporter allosteric modulator ligands, we commenced our part of this collaboration. Five papers related to this project were published in the reporting period, two of which will be highlighted here because of their direct relevance to medication development efforts. Paper #1: In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat. J Pharmacol Exp Ther. 2011 Apr;337(1):218-25. Evidence suggests that elevations in extracellular serotonin (5-HT) in the brain can diminish stimulant effects of dopamine (DA). To assess this proposal, we evaluated the pharmacology of amphetamine analogs (m-fluoroamphetamine, p-fluoroamphetamine, m-methylamphetamine, p-methylamphetamine), which display similar in vitro potency as DA releasers (EC(50) = 24-52 nM) but differ in potency as 5-HT releasers (EC(50) = 53-1937 nM). In vivo microdialysis was used to assess the effects of drugs on extracellular DA and 5-HT in rat nucleus accumbens, while simultaneously measuring ambulation (i.e., forward locomotion) and stereotypy (i.e., repetitive movements). Rats received two intravenous injections of drug, 1 mg/kg at time 0 followed by 3 mg/kg 60 min later. All analogs produced dose-related increases in dialysate DA and 5-HT. All analogs increased ambulation and stereotypy, but drugs causing greater 5-HT release (e.g., p-methylamphetamine) were associated with significantly less forward locomotion. The magnitude of ambulation was positively correlated with extracellular DA (p < 0.001) and less so with the ratio of DA release to 5-HT release (i.e., percentage DA increase divided by percentage 5-HT increase) (p < 0.029). Collectively, our findings are consistent with the hypothesis that 5-HT release dampens stimulant effects of amphetamine-type drugs, but further studies are required to address the precise mechanisms underlying this phenomenon. Paper #2: Serotonin (5-HT) precursor loading with 5-hydroxy-l-tryptophan (5-HTP) reduces locomotor activation produced by (+)-amphetamine in the rat. Drug Alcohol Depend. 2011 Apr 1;114(2-3):147-52. Background, Evidence suggests that increases in synaptic serotonin (5-HT) can reduce the stimulant properties of amphetamine-type drugs. Here we tested the hypothesis that administration of the 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), along with the peripheral decarboxylase inhibitor benserazide, would decrease locomotor effects of (+)-amphetamine. METHODS: Drug treatments were administered to conscious male rats undergoing in vivo microdialysis in nucleus accumbens. During dialysis sampling, rats were housed in chambers equipped with photobeams to detect forward locomotion (i.e., ambulation) and repetitive movements (i.e., stereotypy). Extracellular concentrations of dopamine (DA) and 5-HT were measured by high-pressure liquid chromatography with electrochemical detection.RESULTS:5-HTP (10 & 30 mg/kg, i.p.) plus benserazide (30 mg/kg, i.p.) caused dose-related increases in 5-HT but failed to alter other parameters. (+)-Amphetamine (0.3 & 1.0 mg/kg, i.p.) produced dose-related increases in DA, ambulation and stereotypy. Combined administration of 5-HTP and (+)-amphetamine evoked large elevations in extracellular DA and 5-HT, but caused significantly less ambulation than (+)-amphetamine alone (50% reduction).CONCLUSIONS:Our results confirm that 5-HTP can decrease hyperactivity produced by (+)-amphetamine, even in the presence of elevations in dialysate DA. The data suggest that 5-HTP and (+)-amphetamine may be useful to broadly enhance monoamine function in the clinical setting, while reducing undesirable effects of (+)-amphetamine.

在此报告期间取得了重大进展。与Blough博士合作，我们继续使用体外测定法评估大量新合成化合物。当前的重点是基于苯嗪结构上的DA/5-HT释放器，因为这些化合物在5-HT2B受体上的活性很小。该项目的一个关键方面是避免制造激活5-HT2B受体的化合物，因为该特性与人类心脏瓣膜疾病的发展有关。我们出版了 与Ananthan博士合作，后者获得了NIDA外的资金，以进一步识别多巴胺转运蛋白变构调节器配体，我们开始了这项合作的一部分。与该项目有关的五篇论文在报告期间发表，其中两篇论文将在此处强调，因为它们与药物开发工作的直接相关。 论文＃1：苯丙胺类似物的体内效应揭示了大鼠中性脱甲贝胺传播的血清素能抑制的证据。 J Pharmacol Exp ther。 2011年4月； 337（1）：218-25。 有证据表明，大脑中细胞外5-羟色胺（5-HT）的升高会减少多巴胺（DA）的刺激作用。为了评估这一建议，我们评估了苯丙胺类似物的药理学（M-氟苯丙胺，P-氟苯丙胺，M-甲基苯丙胺，P-甲基苯丙胺），P-Methylamphetamine）在体外效力中表现出与DA疗效相似的（EC（EC（50）= 24-52 Nm）的体外效能，但（EC（EC）与53 NM差异（EC（EC）） nm）。体内微透析用于评估药物对大鼠伏伏核对细胞外DA和5-HT的影响，同时测量移动（即正向运动）和刻板印象（即重复运动）。大鼠接受了两次静脉注射药物，时间为1 mg/kg，然后在60分钟后进行3 mg/kg。所有类似物都会在透析液DA和5-HT中产生与剂量有关的增加。所有类似物都增加了行动和定型观念，但是导致5-HT释放的药物（例如，P-甲基苯丙胺）与正向运动明显相关。行动的大小与细胞外DA（P <0.001）呈正相关，而DA释放与5-HT释放的比率较小（即，DA的百分比增加百分比除以5-HT的百分比增加）（P <0.029）。总的来说，我们的发现与以下假设一致：5-HT释放抑制了苯丙胺型药物的刺激作用，但是需要进一步的研究来解决这种现象的确切机制。 论文＃2：5-羟基-l- tryptophan（5-HTP）羟色胺（5-HT）前体负载减少了大鼠（+） - 苯丙胺产生的运动激活。毒品酒精取决于。 2011年4月1日； 114（2-3）：147-52。 背景，有证据表明，突触5-羟色胺（5-HT）的增加可以降低苯丙胺型药物的刺激特性。在这里，我们检验了以下假设：5-HT前体5-羟基-L- tryptophan（5-HTP）以及外周脱羧酶抑制剂Benserazide，将降低（+） - amphetamine的运动作用。方法：对伏隔核中体内微透析的有意识的雄性大鼠进行药物治疗。在透析采样期间，将大鼠放在配备光束的腔室中，以检测前向运动（即行动）和重复运动（即刻板印象）。通过电化学检测的高压液相色谱法测量了细胞外多巴胺（DA）和5-HT的浓度。分泌物：5-HTP（10＆30 mg/kg，i.p.）加上Benserazide（30 mg/kg，i.p.），导致5-HT的剂量相关，但在5-HT中导致剂量相关，但会导致5-HT的增加。 （+） - 苯丙胺（0.3＆1.0 mg/kg，i.p.）在DA，行动和刻板印象中产生了与剂量相关的增加。 5-HTP和（+） - 苯丙胺的组合施用诱发了细胞外DA和5-HT的较大升高，但与单独的（+） - 单独的苯丙胺相比（降低50％）。结论：我们的结果证实，5-HTP可以证实5-HTP可以降低（+） - 苯丙胺 - 苯丙胺的多动量，甚至在疾病中降低了DA的升高。数据表明，5-HTP和（+） - 苯丙胺可能在临床环境中广泛增强单胺功能有用，同时减少（+） - 苯丙胺的不良作用。