DRUG DEVELOPMENT

药物开发

• 批准号: 3752846
• 负责人: J M WITKIN
• 金额: --
• 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/3752846
• 关键词: NMDA receptors; PCP receptor; anticonvulsants; behavioral habituation /sensitization; cocaine; dopamine; dopamine antagonists; dopamine receptor; drug abuse chemotherapy; drug addiction antagonist; drug design /synthesis /production; drug receptors; drug screening /evaluation; glutamate receptor; neurotransmitter transport; psychopharmacology; receptor binding; reinforcer

These studies are designed to provide preclinical information for the development of medications to be used in the treatment of drug abuse and drug abuse-related toxicities. The primary focus of this work is to determine pharmacological means for modulating behavioral and toxic actions of abused compounds, and to evaluate new chemical entities (synthesized in house and from outside sources) for safety and efficacy in the design of potential rational treatment strategies. Work in this area is also expected to provide increased understanding of the mechanisms of action of drugs of abuse. The primary findings and implications for the current year are: (1) We have extended initial observations that certain sigma-receptor ligands can antagonize some of the acute behavioral effects of cocaine by demonstrating this effect with a highly selective sigma ligand and by showing that this compound can also attenuate the behavioral effects of repeated cocaine exposure (sensitization) and cocaine-induced convulsions. We have also found that certain sigma ligands bind to the dopamine transporter. Ongoing studies are focusing on identifying significant features of sigma ligands that imbue them with the ability to block effects of cocaine and defining a mechanism for the cocaine blockade. A host of sigma ligands, some with excellent affinity and selectivity have been synthesized to aid in this effort. (2) A variety of compounds proposed by NIDA as potential treatments for cocaine abuse are being examined in preclinical screens for safety and efficacy as potential treatments for cocaine abuse. (3) Psychomotor stimulant effects of abused drugs like cocaine may be amenable to pharmacological antagonism through glutamate receptors. We have discovered some such compounds with efficacy as antagonists of the stimulant effects of cocaine and of methamphetamine and have uncovered differences among these compounds which should help shed light on the interactions between dopaminergic and excitatory amino acid pathways. (4) In accord with clinical experience, we have used a model developed in our lab of cocaine-induced convulsions that are relatively insensitive to standard anticonvulsants to discover novel and efficacious treatments for drug-resistant cocaine toxicities. Thus far, a host of glutamate antagonists have been shown to be effective and some appear to have a reasonable margin of safety for this therapeutic endpoint. Two classes of compounds have been identified for further drug development, low affinity NMDA antagonists and functional antagonists of the glycine-linked site of the NMDA receptor. (5) Pharmacological studies have tentatively identified a population of dopamine D1 receptors in the periphery that may be linked to the acute lethal effects of cocaine. Compounds necessary for further investigations in this area have been synthesized and structure-activity relationships, and in vitro and in vivo pharmacological characterization of these compounds is underway.

这些研究旨在为以下疾病提供临床前信息： 开发用于治疗药物滥用的药物和 与药物滥用相关的毒性。这项工作的主要重点是 确定调节行为和毒性的药理学方法 滥用化合物的作用，并评估新的化学实体 （在内部和外部合成）以确保安全性和有效性 设计潜在的合理治疗策略。 从事此工作 预计该领域还将加深人们对 滥用药物的作用机制。 主要发现和 对今年的影响是： (1) 我们延长了最初的 观察到某些西格玛受体配体可以拮抗某些 通过证明可卡因的急性行为影响 一种高度选择性的西格玛配体，并表明该化合物可以 还可以减轻反复接触可卡因的行为影响 （致敏）和可卡因引起的抽搐。 我们还发现 某些西格玛配体与多巴胺转运蛋白结合。 正在进行的研究 专注于识别西格玛配体的显着特征 使他们能够阻止可卡因的影响并定义 可卡因封锁机制。 许多西格玛配体，其中一些带有 优异的亲和力和选择性已被合成以帮助实现这一点 努力。 (2) NIDA提出的多种潜在化合物 临床前筛查正在检查可卡因滥用的治疗方法 作为可卡因滥用的潜在治疗方法的安全性和有效性。 (3) 可卡因等滥用药物的精神运动兴奋作用可能是 易于通过谷氨酸受体产生药理学拮抗作用。 我们 已经发现了一些具有作为拮抗剂功效的此类化合物 可卡因和甲基苯丙胺的兴奋作用，并已被发现 这些化合物之间的差异应该有助于阐明 多巴胺能和兴奋性氨基酸途径之间的相互作用。 (4)根据临床经验，我们采用了开发的模型 在我们的实验室中，可卡因引起的抽搐相对不敏感 标准抗惊厥药以发现新颖有效的治疗方法 用于耐药可卡因毒性。 迄今为止，大量谷氨酸 拮抗剂已被证明是有效的，并且有些似乎具有 该治疗终点的合理安全边际。 两班 的化合物已被确定用于进一步的药物开发，低 亲和力 NMDA 拮抗剂和功能性拮抗剂 NMDA 受体的甘氨酸连接位点。 (5)药理研究 初步鉴定出一组多巴胺 D1 受体 外周可能与可卡因的急性致死作用有关。 该领域进一步研究所需的化合物已被 合成和构效关系，以及体外和体内 这些化合物的体内药理学表征正在进行中。