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: 8267443
• 负责人: Nurulain T Zaveri
• 金额: $ 1.05万
• 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/8267443
• 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; 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）：临床需要对药物滥用有效的药物滥用合并症。对多种滥用物质的成瘾是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机制的作用。此外，患者的药物成瘾有几个阶段（获得、戒断、渴望、复发），单靠一种药物的单一作用机制可能无法充分治疗。因此，针对补充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途径。一个典型的例子是丁丙诺啡，一种非选择性阿片受体部分激动剂/卡帕拮抗剂/伤害肽受体部分激动剂，临床上对可卡因和海洛因成瘾有效，最近也显示对酒精滥用有效。丁丙诺啡在痛觉啡受体上的活性被认为在治疗可卡因和酒精成瘾方面发挥了作用。已知伤害感受素受体NOP参与奖励通路，伤害感受素/孤啡肽FQ （N/OFQ）是NOP受体的内源性激动剂，已被证明可阻断对几种滥用药物的自我给药和条件位置偏好（CPP）的获得；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断吗啡和乙醇的位置偏好和药物寻找的恢复。我们假设，同时靶向NOP受体和阿片受体，并具有理想的NOP激动剂/阿片活性混合谱的化合物将为多种药物成瘾治疗提供新的药物治疗方法。我们的初步数据表明，具有NOP完全激动剂和mu阿片受体弱部分激动剂活性的化合物可以减弱吗啡CPP的获得。我们已经开发了几种新的NOP激动剂，并在NOP对阿片受体的亲和力和选择性方面具有广泛的结构-活性关系。以此为基础，我们建议设计NOP/阿片类药物“多重”配体，这些配体具有所需的混合活性特征，可作为药物滥用治疗的潜在药物。我们的具体目标是(i)设计新的NOP/阿片样物质混合配体，优化NOP完全激动剂活性和选择的阿片样物质受体功效，合适的药代动力学特性和血脑屏障穿透性；（ii）在体外表征混合配体的NOP和阿片样物质亲和力和功能特征，评估其代谢稳定性并确定整体受体特征；（iii）在体内检查具有选定特征的配体对吗啡和可卡因CPP的获得以及药物和应激诱导的吗啡和可卡因CPP恢复的影响。我们期望能够鉴定出几种新型的nop -阿片类药物混合配体，这些配体具有理想的疗效和合适的药物样特征，可以进一步开发用于治疗多种药物成瘾的药物疗法。