Discovery of Bifunctional NOP/Opioid Receptor Ligands for Drug Abuse Therapy

描述(由申请人提供)：临床上需要能有效对抗药物滥用的药物滥用药物。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、渴求、复发)，可能无法通过单一药物的单一作用机制进行充分治疗。因此，针对双重或多种互补药理机制的药物治疗可能为有效治疗药物成瘾提供新的途径。丁丙诺啡就是一个很好的例子，它是一种非选择性的MU阿片受体部分激动剂/kappa拮抗剂/伤害素受体部分激动剂，在临床上对可卡因和海洛因成瘾有效，最近被证明对酒精滥用也有效。丁丙诺啡在伤害素受体上的活性被认为在其治疗可卡因和酒精成瘾的疗效中发挥了作用。已知伤害素受体NOP参与奖赏通路，NOP受体的内源性激动剂伤害素/孤啡肽FQ(N/OFQ)已被证明可阻断自我给药和对几种滥用药物的条件性位置偏爱(CPP)的获得，特别是吗啡、可卡因、苯丙胺和酒精。一种小分子NOP激动剂也被证明可以阻止吗啡和乙醇的获得，位置偏爱和恢复药物寻找。我们推测，既针对NOP受体又针对阿片受体的化合物，具有理想的NOP激动剂/阿片类药物活性的混合特征，将为多药成瘾治疗提供新的药物治疗方法。我们的初步数据显示，含有NOP全激动剂和MU阿片受体弱部分激动剂活性的化合物可引起吗啡CPP的获得。我们已经开发了几种新的NOP激动剂，并对NOP与阿片受体的亲和力和选择性具有广泛的构效关系。以此为基础，我们建议设计具有理想混合活性的NOP/阿片“多”配体，作为药物滥用治疗的潜在药物。我们的具体目标是(I)设计具有NOP全部激动剂活性和选定阿片受体有效性、合适的药代动力学特性和血脑屏障的新型NOP/阿片混合配体；(Ii)在体外表征混合配体的NOP和阿片亲和力和功能图谱，评估其代谢稳定性并确定整体受体图谱；(Iii)在体内检测具有选定图谱的配体对吗啡和可卡因CPP的获得以及对药物和应激诱导的吗啡和可卡因CPP的恢复的影响。我们期望能找到几种新的NOP-阿片混合配体，它们具有理想的疗效和合适的类药物特性，可以作为治疗多药成瘾的药物疗法进一步开发。 公共卫生相关性：对多种滥用物质上瘾在成瘾者中相当普遍，是一个严重的治疗问题和未得到满足的临床需求。开发在单一制剂中具有多个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的治疗选择。本申请中提出的双功能NOP/阿片受体配体的发现，提供了将已知互补药理和广泛的抗成瘾作用的双重靶向活性结合成可开发为治疗多药成瘾的药物的单一药物的优势。

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.