Discovery of Bifunctional NOP/Opioid Receptor Ligands for Drug Abuse Therapy

用于药物滥用治疗的双功能 NOP/阿片受体配体的发现

• 批准号: 8712437
• 负责人: Nurulain T Zaveri
• 金额: $ 70.94万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712437
• 关键词: Affect; Affinity; Agonist; Alcohol abuse; Alcohol dependence; Alcohols; Amphetamines; Attenuated; Binding; Biological Assay; Biology; Blood - brain barrier anatomy; Buprenorphine; Characteristics; Clinical; Cocaine; Cocaine Dependence; Complex; Data; Development; Drug Addiction; Drug Kinetics; Drug abuse; Ethanol; Evaluation; Foundations; Heroin Dependence; Human; In Vitro; Intervention; Lead; Ligands; Liver Microsomes; Metabolic; Modeling; Morphine; Mus; NIH Program Announcements; Narcotic Antagonists; Opiate Addiction; Opioid; Opioid Receptor; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Plasma; Play; Process; Property; Rattus; Relapse; Rewards; Role; Self Administration; Series; Stress; Structure-Activity Relationship; Substance abuse problem; System; Tail; Withdrawal; Work; addiction; analog; base; clinical efficacy; comparative; craving; design; drug abuse therapy; drug candidate; drug discovery; drug of abuse; drug reward; effective therapy; improved; in vivo; mu opioid receptors; multidrug abuse; nociceptin; nociceptin receptor; novel; novel strategies; pharmacophore; preference; programs; receptor; response; scaffold; small molecule; success

PROJECT SUMMARY There is a clinical need for substance abuse medications that are effective against comorbid drug abuse. Addiction to multiple abused substances presents a complex clinical problem, treatment for which may require multiple pharmacological approaches via multiple mechanisms of action. Further, there are several phases of drug addiction in patients (acquisition, withdrawal, craving, relapse) that may not adequately treated by a single mechanism of action of a single drug. Therefore, pharmacotherapies that target dual or multiple mechanisms of complementary pharmacology may provide novel approaches for the effective treatment of drug addiction. A case in point is buprenorphine, a nonselective mu opioid receptor partial agonist/kappa antagonist/nociceptin receptor partial agonist, which is clinically effective against cocaine and heroin addiction, and recently shown to be effective against alcohol abuse as well. Buprenorphine's activity at the nociceptin receptor is thought to play a role in its efficacy in treating cocaine and alcohol addiction. The nociceptin receptor NOP is known to be involved in reward pathways, and nociceptin/Orphanin FQ (N/OFQ), the endogenous agonist for the NOP receptor, has been shown to block self-administration and acquisition of conditioned place preference (CPP) to several drugs of abuse; in particular, morphine, cocaine, amphetamines, and alcohol. A small-molecule NOP agonist has also been shown to block acquisition of morphine and ethanol place preference and reinstatement of drug-seeking. We hypothesize that compounds that target both the NOP receptor and the opioid receptors, and have a desirable mixed profile of NOP agonist/opioid activity, will provide new pharmacotherapeutic approaches for polydrug addiction treatment. Our preliminary data show that a compound with NOP full agonist and mu opioid receptor weak partial agonist activity attentuates acquisition of morphine CPP. We have developed several novel NOP agonists and have extensive structure-activity relationships for NOP affinity and selectivity versus opioid receptors. Using this as a foundation, we propose to design NOP/opioid 'multiple' ligands that have a desired mixed profile of activity as potential agents for drug abuse therapy. Our specific aims are to (i) design novel NOP/opioid mixed ligands with an optimized profile of NOP full agonist activity and selected opioid receptor efficacy, suitable pharmacokinetic properties and blood-brain barrier penetration (ii) to characterize the mixed ligands in vitro for their NOP and opioid affinity and functional profile, evaluate their metabolic stability and determine an overall receptor profile; and (iii) to examine ligands with selected profiles in vivo for their effect on the acquisition of morphine and cocaine CPP, and on drug- and stress-induced reinstatement of morphine and cocaine CPP. We expect that we will identify several novel NOP-opioid mixed ligands with desirable efficacy profiles and suitable drug-like characteristics for further development as pharmacotherapies for the treatment of polydrug addiction.

项目摘要 临床上需要对共病药物滥用有效的药物滥用药物。 对多种滥用物质成瘾是一个复杂的临床问题，治疗可能需要 通过多种作用机制的多种药理学方法。此外，有几个阶段， 患者的药物成瘾（获得、戒断、渴望、复发）可能无法通过单一药物充分治疗 单一药物的作用机制。因此，靶向双重或多重机制的药物疗法 补充药理学的研究可能为有效治疗药物成瘾提供新的途径。一 一个恰当的例子是丁丙诺啡，一种非选择性μ阿片受体部分激动剂/κ拮抗剂/伤害感受素 受体部分激动剂，临床上对可卡因和海洛因成瘾有效，最近显示， 对酒精滥用也有效。丁丙诺啡对痛敏受体的作用被认为是 在治疗可卡因和酒精成瘾方面的作用。已知伤害感受素受体NOP是 参与奖赏途径，以及伤害感受素/孤啡肽FQ（N/OFQ），NOP的内源性激动剂， 受体，已被证明可以阻断自我管理和获得条件性位置偏好（CPP）， 滥用的几种药物;特别是吗啡、可卡因、安非他明和酒精。一种小分子NOP 一种激动剂也被证明可以阻断吗啡和乙醇位置偏爱的获得和恢复 寻找毒品。我们假设同时靶向NOP受体和阿片受体的化合物， 并具有所需的NOP激动剂/阿片样物质活性的混合特征，将提供新的药理学 多种药物成瘾治疗的方法。我们的初步数据显示，一种具有NOP完全激动剂的化合物 μ阿片受体弱的部分激动剂活性减弱吗啡CPP的获得。我们有 开发了几种新的NOP激动剂，并对NOP亲和力具有广泛的结构-活性关系， 对阿片受体的选择性。以此为基础，我们建议设计NOP/阿片类药物"多重" 作为药物滥用治疗的潜在药剂具有所需混合活性特征的配体。我们的具体 目的是（i）设计具有优化的NOP完全激动剂活性分布的新型NOP/阿片样物质混合配体， 选择的阿片样物质受体功效、合适的药代动力学性质和血脑屏障渗透（ii）， 在体外表征混合配体的NOP和阿片样物质亲和力和功能概况，评估其 代谢稳定性并确定总体受体谱;和（iii）检查具有选定谱的配体 在体内研究了它们对吗啡和可卡因CPP获得的影响，以及对药物和应激诱导的CPP的影响。 吗啡和可卡因CPP的恢复。我们希望我们将确定几种新的NOP-阿片类药物混合物， 配体具有期望的功效特征和合适的药物样特征，用于进一步开发， 治疗多种药物成瘾的药物疗法。