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: 8848273
• 负责人: Nurulain T Zaveri
• 金额: $ 1.11万
• 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/8848273
• 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.

项目总结 临床上需要能够有效对抗药物滥用的药物滥用药物。 对多种滥用药物的上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方法。此外，还有几个阶段 患者的药物成瘾(获得性、戒断、渴求、复发)可能无法通过单一的 单一药物的作用机制。因此，针对双重或多种机制的药物疗法 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。一个 丁丙诺啡就是一个很好的例子，它是一种非选择性MU阿片受体部分激动剂/kappa拮抗剂/伤害素 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 对酗酒也是有效的。丁丙诺啡在伤害素受体上的活性被认为在 在治疗可卡因和酒精成瘾方面的作用。伤害素受体NOP是已知的 参与奖赏通路，以及NOP的内源性激动剂伤害素/孤啡肽FQ(N/OFQ) 受体，已被证明阻止自我给药和获得条件性位置偏爱(CPP)。 几种滥用药物；尤其是吗啡、可卡因、安非他明和酒精。一种小分子NOP 激动剂也被证明可以阻止吗啡和乙醇的位置偏爱和恢复 在寻找毒品的时候。我们假设针对NOP受体和阿片受体的化合物， 并且具有理想的NOP激动剂/阿片类药物活性的混合特征，将提供新的药物治疗 多药成瘾的治疗方法。我们的初步数据显示，一种含有NOP完全激动剂的化合物 Mu阿片受体部分激动剂活性较弱，提示吗啡CPP的获得。我们有 开发了几种新型的NOP激动剂，并具有广泛的NOP亲和力和 选择性与阿片受体。以此为基础，我们提出了NOP/阿片类药物的多重设计 具有理想的混合活性的配体，作为药物滥用治疗的潜在试剂。我们的特定 目的是(I)设计新型的NOP/阿片混合配体，具有优化的NOP全激动剂活性和 选择阿片受体的疗效、合适的药代动力学特性和血脑屏障通透性(II) 体外表征混合配体的NOP和阿片亲和力和功能谱，评估其 代谢稳定性和确定整体受体图谱；以及(Iii)用选定的图谱检查配体 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影响 恢复吗啡和可卡因CPP。我们预计我们将鉴定出几种新的NOP-阿片混合物 具有理想疗效和适合进一步开发的类药物特性的配体，如 治疗多药成瘾的药物疗法。

项目成果

Differential In Vitro Pharmacological Profiles of Structurally Diverse Nociceptin Receptor Agonists in Activating G Protein and Beta-Arrestin Signaling at the Human Nociceptin Opioid Receptor.

结构多样的伤害感受肽受体激动剂激活人伤害感受肽阿片受体 G 蛋白和 β-抑制蛋白信号传导的差异体外药理学特征。

• DOI: 10.1124/molpharm.120.000076
• 发表时间: 2021
• 期刊: Molecular pharmacology
• 影响因子: 3.6
• 作者: Lu,JamesJ;Polgar,WillmaE;Mann,Anika;Dasgupta,Pooja;Schulz,Stefan;Zaveri,NurulainT
• 通讯作者: Zaveri,NurulainT

A Novel and Selective Nociceptin Receptor (NOP) Agonist (1-(1-((cis)-4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)methanol (AT-312) Decreases Acquisition of Ethanol-Induced Conditioned Place Preference in Mice.

新型选择性伤害感受肽受体 (NOP) 激动剂 (1-(1-((顺)-4-异丙基环己基)哌啶-4-基)-1H-吲哚-2-基)甲醇 (AT-312) 减少乙醇的获取

• DOI: 10.1111/acer.13575
• 发表时间: 2018
• 期刊: Alcoholism, clinical and experimental research
• 作者: Zaveri,NurulainT;Marquez,PaulV;Meyer,MichaelE;Polgar,WillmaE;Hamid,Abdul;Lutfy,Kabirullah
• 通讯作者: Lutfy,Kabirullah

The Nociceptin Receptor (NOP) Agonist AT-312 Blocks Acquisition of Morphine- and Cocaine-Induced Conditioned Place Preference in Mice.

伤害感受肽 (NOP) 激动剂 AT-312 可阻止小鼠获得吗啡和可卡因诱导的条件性位置偏好。

• DOI: 10.3389/fpsyt.2018.00638
• 发表时间: 2018
• 期刊: Frontiers in psychiatry
• 影响因子: 4.7
• 作者: Zaveri,NurulainT;Marquez,PaulV;Meyer,MichaelE;Hamid,Abdul;Lutfy,Kabirullah
• 通讯作者: Lutfy,Kabirullah