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: 7767102
• 负责人: Nurulain T Zaveri
• 金额: $ 62.26万
• 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 2014-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7767102
• 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; 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; Opiates; 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; public health relevance; receptor; response; scaffold; small molecule; success

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Addiction to multiple abused substances is quite commonplace among addicts and represents a serious treatment problem and an unmet clinical need. Development of pharmacotherapies that have multiple targeted mechanisms of action in a single agent can provide a single new treatment option for the various aspects of the addiction process and/or for patients addicted to multiple drugs. The discovery of bifunctional NOP/opioid receptor ligands, as proposed in this application, offers the advantage of combining dual-targeted activities of known complementary pharmacology and broad anti-addictive effects, into single agents that can be developed as pharmacotherapies for polydrug addiction.

描述（由申请人提供）：临床上需要有效对抗共病药物滥用的药物滥用药物。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，患者的药物成瘾有几个阶段（获得、戒断、渴望、复发），可能无法通过单一药物的单一作用机制得到充分治疗。因此，靶向互补药理学的双重或多重机制的药物治疗可能为有效治疗药物成瘾提供新的方法。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，其在临床上对可卡因和海洛因成瘾有效，并且最近显示对酒精滥用也有效。丁丙诺啡对痛敏素受体的活性被认为在其治疗可卡因和酒精成瘾的功效中发挥作用。已知伤害感受素受体NOP参与奖赏途径，并且伤害感受素/孤啡肽FQ（N/OFQ）（NOP受体的内源性激动剂）已显示阻断对若干滥用药物（特别是吗啡、可卡因、安非他明和酒精）的自我施用和条件性位置偏好（CPP）的获得。小分子NOP激动剂也被证明可以阻止吗啡和乙醇位置偏好的获得和药物寻求的恢复。我们假设，化合物的目标是NOP受体和阿片受体，并具有理想的混合配置文件的NOP激动剂/阿片类药物的活性，将提供新的药理学方法的多药成瘾治疗。我们的初步数据表明，具有NOP完全激动剂和μ阿片受体弱部分激动剂活性的化合物减弱吗啡CPP的获得。我们已经开发了几种新的NOP激动剂，并对阿片受体的NOP亲和力和选择性具有广泛的结构-活性关系。以此为基础，我们建议设计NOP/阿片类药物的“多”配体，具有所需的混合配置文件的活动作为药物滥用治疗的潜在代理。我们的具体目标是（i）设计新型NOP/阿片类混合配体，其具有NOP完全激动剂活性和所选阿片类受体功效的优化特征、合适的药代动力学性质和血脑屏障穿透性（ii）在体外表征混合配体的NOP和阿片类亲和力和功能特征，评价它们的代谢稳定性并确定总体受体特征;和（iii）检查具有所选特征的配体在体内对吗啡和可卡因CPP的获得以及对药物和应激诱导的吗啡和可卡因CPP的恢复的作用。我们预计我们将识别出几种新型的NOP-阿片类混合配体，它们具有理想的功效特征和合适的药物样特征，可进一步开发为治疗多药成瘾的药物疗法。 公共卫生关系：对多种滥用物质成瘾在成瘾者中相当普遍，是一个严重的治疗问题和未满足的临床需求。开发在单一药剂中具有多种靶向作用机制的药物疗法可以为成瘾过程的各个方面和/或对多种药物成瘾的患者提供单一的新治疗选择。如本申请中提出的双功能NOP/阿片样物质受体配体的发现提供了将已知互补药理学的双靶向活性和广泛的抗成瘾作用组合成可开发为用于多种药物成瘾的药物疗法的单一药剂的优点。