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

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