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.

项目摘要 临床需要滥用药物，这些药物有效地防止滥用毒品。 对多种滥用物质的成瘾提出了一个复杂的临床问题，治疗可能需要 多种药理方法通过多种作用机制。此外，还有几个阶段 患者的药物成瘾（收购，戒断，渴望，复发）可能无法通过一个单一的治疗 单一药物的作用机理。因此，针对双重或多种机制的药物疗法 补充药理学可以提供有效治疗药物成瘾的新方法。一个 一个典型的是丁丙诺啡，一种非选择性的MU阿片受体部分激动剂/kappa拮抗剂/诺耐匹素 受体部分激动剂，对可卡因和海洛因成瘾具有临床有效，最近证明 也要有效滥用酗酒。丁丙诺啡在Nociteptin受体中的活动被认为可以发挥作用 其在治疗可卡因和酒精成瘾中的功效中的作用。 Nocteptin受体NOP已知为 参与奖励途径和NociTptin/Orphanin FQ（N/OFQ），NOP的内源性激动剂 受体已被证明可以阻止有条件地位偏好（CPP）的自我管理和获取 几种滥用药物；特别是吗啡，可卡因，苯丙胺和酒精。小分子的NOP 还显示激动剂可以阻止吗啡和乙醇位置的偏好和恢复原状的获取 寻求毒品。我们假设，靶向NOP受体和阿片受体的化合物， 并具有NOP激动剂/阿片类药物活动的理想混合曲线，将提供新的药物治疗 多药瘾治疗方法。我们的初步数据表明，具有NOP完全激动剂的化合物 和MU阿片类受体弱部分激动剂活性专注于吗啡CPP的获取。我们有 开发了几种新型的NOP激动剂，并具有广泛的结构活性关系，以实现NOP亲和力和 选择性与阿片受体。以此为基础，我们建议设计NOP/阿片类药物“多重” 具有期望活性混合概况的配体作为药物滥用疗法的潜在药物。我们的具体 目的是（i）设计新颖的NOP/阿片类混合配体，具有NOP全部激动剂活动和 选定的阿片类受体功效，合适的药代动力学特性和血脑屏障渗透（II） 表征体外混合配体的NOP和阿片类药物亲和力和功能谱，评估其 代谢稳定性并确定整体受体谱； （iii）检查具有选定曲线的配体 在体内对吗啡和可卡因CPP的获取以及药物和应激诱导的 恢复吗啡和可卡因CPP。我们希望我们将确定几种新型的NOP-Apoid混合 具有理想疗效曲线和合适的药物样特征的配体，以进一步发展 用于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