Design and synthesis of drugs acting on central and peripheral tissues

作用于中枢和外周组织的药物的设计与合成

• 批准号: 7593323
• 负责人: Kenner C Rice
• 金额: $ 466.34万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593323
• 关键词: Absence of pain sensation; Abstinence; Accounting; Acute; Adverse effects; Affinity; Agonist; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Analgesics; Animals; Antidepressive Agents; Appearance; Area; Attention; Attenuated; Behavior; Behavioral; Biogenic Amines; Biological Assay; Brain; Cannabinoids; Carbon; Chemicals; Class; Cocaine; Complex; Cookbook; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Dependence; Development; Disease; Dopamine; Dose; Drug abuse; Endorphins; Ethanol; Ethanol dependence; Goals; Hallucinogens; Heroin; Heroin Abuse; Hormone Antagonists; Human; Hybrids; Ligands; Mediating; Methamphetamine; Modeling; Morphine; Naltrexone; Narcotic Abuses; Narcotic Antagonists; Narcotics; Nitrogen; Nucleus Accumbens; Numbers; Opiates; Opioid; Opioid Peptide; Opioid Receptor; Oxycodone; Pain; Patients; Peptides; Peptoids; Peripheral; Pharmaceutical Preparations; Phenethylamine; Phenethylamines; Physiological; Play; Positron-Emission Tomography; Prevention; Publications; Purpose; Rattus; Regulation; Relapse; Relative (related person); Reporting; Research; Research Personnel; Role; Self Administration; Self-Administered; Series; Serotonin Receptor 5-HT1A; Serotonin Receptor 5-HT2A; Skeleton; Stimulus; Stress; Structure-Activity Relationship; Students; System; Time; Tissues; Tryptamines; United States National Institutes of Health; Withdrawal; Yohimbine; alcohol effect; alcohol preferring rats; alcohol reinforcement; alcohol response; alcohol seeking behavior; antalarmin; chemical synthesis; chronic pain; delta opioid receptor; design; dipropyltryptamine; drinking; drug of abuse; drug production; drug synthesis; ecstasy; enantiomer; endogenous opioids; immune function; inhibitor/antagonist; insight; interest; kappa opioid receptors; multidisciplinary; neuropsychiatry; novel; phenylmorphan; prescription document; prescription procedure; prevent; programs; receptor; reinforced behavior; response; reuptake; serotonin receptor; tool; tryptamine; tryptamine analog

The opioid receptor endorphin system consists of saturable, enantioselective, high affinity mu, delta and kappa opioid receptor types located in anatomically well defined areas of the mammalian CNS with the numerous endogenous opioid peptides (endorphins) which subserve these receptors. These receptors have been cloned and convincing pharmacological evidence now supports at least two subtypes of each. These results present many opportunities for research highly relevant to drug abuse and for the development of new medications that act on these receptors. The opioid receptor endorphin system mediates the analgesic, euphoric and addictive effects of narcotic drugs and contributes to regulation of numerous physiologic and behavioral functions in its normal state including regulation of dopamine (DA) levels in the nucleus accumbens (NAC) and expression of the effects of alcohol. This system is dysregulated by the abuse of heroin, cocaine and prescription narcotics and the abuse of these drugs is presently an enormous problem. The abuse of prescription narcotics alone, especially oxycodone (oxycontin) surged 308% during 2000-2005 with 9.5% of twelfth grade students in 2004 having abused prescription narcotics within the last year. Recently however, encouraging studies have shown that moderately selective delta opioid antagonists suppress (a) cocaine seeking behavior, (b) heroin self-administration and (c) the development of tolerance and dependence to the mu agonist morphine. The former two observations strongly indicate that highly selective delta receptor antagonists might be valuable medications for the treatment and prevention of human cocaine and narcotic abuse and perhaps other undesirable reinforcing behaviors. The latter observation suggests that a drug showing a mu agonist-delta antagonist profile might produce strong analgesia without producing tolerance and dependence thus allowing continuous treatment of chronic pain. Animal studies with peptide-nonpeptide hybrid molecules (peptoids) have validated this hypothesis. These molecules showed strong analgesia with substantially reduced tolerance and dependence relative to morphine but are only effective when administered directly into the brain. We have experimental evidence that delta opioid agonists may be useful antidepressants and can also enhance immune function. In addition, kappa opioid antagonists have recently been found to have antidepressant-like activity and prevent stress-induced relapse in a rat model of cocaine self-administration. The exploitation of these and other similarly intriguing observations now requires novel, exquisitely selective, nonpeptide ligands as research tools and potential medications. These new tools will enable the study of many questions of fundamental importance concerning the function of mu, delta and kappa opioid receptor subtypes and how drugs interact with their receptors to elicit these functions. We have continued to design, synthesize and evaluate novel drugs for this purpose during the reporting period. The 5-phenylmorphans are a particularly interesting class of opioid receptor agonists that were originated by Everette May at NIH in 1955. We recently identified a mu agonist-delta antagonist and a delta inverse agonist in this series. Very few nonpeptide opioids in any structural class with this profile are known. We also reported another mu agonist-delta antagonist and an exceedingly potent mu agonist in this series. The latter is by far the most potent 5-phenylmorphan agonist known showing more that 1000 times the potency of morphine in the single dose suppression of morphine abstinence assay. The diverse profiles obtained in this series illustrate the importance of subtle changes on the carbon-nitrogen skeleton and careful attention to stereochemical detail and provide important leads toward pain medications with reduced side effects. Our studies in the role of stress in drug abuse have continued. We and others have shown that stress can play an important role in promoting drug self-administration and relapse to drug abuse. The corticotropin releasing hormone receptor (CRHR1) plays a central role in initiation of the response to stress. We showed that the CRHR1 antagonist antalarmin reduced ethanol self-administration in ethanol-dependent rats after acute ethanol withdrawal but not in ethanol nondependent rats. In related study, we found that antalarmin attenuated yohimbine stress induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Finally, we showed that spontaneous ethanol self-administration of nondependent Sardinian alcohol-preferring rats was suppressed by the opiate antagonist naltrexone and therefore opioid dependent. The CRHR1 antagonist LWH-63 reduced withdrawal-induced drinking in these rats but not spontaneous drinking in nondependent rats suggesting opioid and CRHR1 receptors play different roles in ethanol reinforcement. These studies suggest that CRHR1 antagonists may be useful in the treatment of human alcohol dependence in conjunction with naltrexone and that optimal treatment may vary between different subtypes of patients. The abuse of methylenedioxymethamphetamine (MDMA) and related hallucinogenic drugs is another serious problem. Recent data from the Drug Enforcement Administration show the appearance of novel hallucinogenic phenethylamines and tryptamines either previously encountered in insignificant amounts or not seen at all. This is due in part to the recent publication of cookbook chemical syntheses and detailed accounts of the doses used and hallucinogenic effects seen in humans for almost all of the 179 phenethylamine and 53 tryptamine analogs that were synthesized and self-administered by A. T. Shulgin and his associates during more than 30 years. These are disturbing developments that substantially aid and encourage clandestine drug production and may presage a resurgence in hallucinogenic drug abuse. We have begun a program to synthesize and evaluate a number of hallucinogenic agents and their antagonists. We developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907, its carbon-11 precursor for positron emission tomography and their enantiomers. We have studied the discriminative stimulus effects of several of these drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. Our results show that the 5-HT2A receptor is involved in psilocybin-induced stimulus control in rat. This receptor was also found to play a major role in the agonist action of N,N-dipropyltryptamine with a possible contribution of the 5-HT1A receptor. Lastly, we reviewed (a) the potential uses of corticotropin-releasing hormone antagonists and (b) the structure-activity relationships of biogenic amine reuptake inhibitors (potential cocaine and methamphetamine treatment agents) during the reporting period.

阿片受体内啡肽系统由位于哺乳动物中枢神经系统解剖学明确区域的可饱和、对映选择性、高亲和力 mu、delta 和 kappa 阿片受体类型组成，并具有促进这些受体的众多内源性阿片肽（内啡肽）。这些受体已被克隆，令人信服的药理学证据现在支持每种受体至少有两种亚型。这些结果为与药物滥用高度相关的研究以及开发作用于这些受体的新药物提供了许多机会。阿片受体内啡肽系统介导麻醉药物的镇痛、欣快和成瘾作用，并有助于调节正常状态下的许多生理和行为功能，包括伏隔核（NAC）中多巴胺（DA）水平的调节和效应的表达酒精。该系统因海洛因、可卡因和处方麻醉药的滥用而失调，这些药物的滥用目前是一个巨大的问题。仅处方麻醉药的滥用，特别是羟考酮（奥施康定）在 2000 年至 2005 年期间激增了 308%，2004 年 9.5% 的十二年级学生在去年滥用了处方麻醉药。 然而，最近令人鼓舞的研究表明，中等选择性的 δ 阿片拮抗剂可抑制 (a) 可卡因寻求行为、(b) 海洛因自我给药和 (c) 对 mu 激动剂吗啡产生耐受和依赖。前两个观察强烈表明，高选择性δ受体拮抗剂可能是治疗和预防人类可卡因和麻醉品滥用以及其他不良强化行为的有价值的药物。后一个观察结果表明，显示 mu 激动剂-δ 拮抗剂特性的药物可能会产生强烈的镇痛作用，而不产生耐受性和依赖性，从而允许持续治疗慢性疼痛。肽-非肽杂合分子（类肽）的动物研究证实了这一假设。这些分子表现出很强的镇痛作用，与吗啡相比，其耐受性和依赖性大大降低，但只有直接给药到大脑时才有效。我们有实验证据表明 δ 阿片受体激动剂可能是有用的抗抑郁药，并且还可以增强免疫功能。此外，最近发现卡帕阿片拮抗剂具有抗抑郁样活性，可以在可卡因自我给药的大鼠模型中预防应激诱导的复发。对这些和其他类似有趣的观察结果的利用现在需要新颖的、精妙选择性的非肽配体作为研究工具和潜在的药物。这些新工具将能够研究许多与 mu、delta 和 kappa 阿片受体亚型的功能以及药物如何与其受体相互作用以引发这些功能的重要问题。报告期内，我们继续为此目的设计、合成和评价新药。 5-苯基吗啡烷是一类特别有趣的阿片受体激动剂，由 NIH 的 Everette May 于 1955 年发明。我们最近在该系列中鉴定了一种 mu 激动剂-δ 拮抗剂和一种 δ 反激动剂。具有这种特征的任何结构类别中已知的非肽阿片类药物非常少。我们还报道了本系列中的另一种 mu 激动剂-δ 拮抗剂和一种非常有效的 mu 激动剂。后者是迄今为止已知最有效的 5-苯基吗啡酮激动剂，在单剂量抑制吗啡戒断试验中显示出超过吗啡 1000 倍的效力。本系列中获得的不同概况说明了碳氮骨架的微妙变化和仔细关注立体化学细节的重要性，并为减少副作用的止痛药物提供了重要线索。 我们关于压力在药物滥用中的作用的研究仍在继续。我们和其他人已经证明，压力可以在促进药物自我给药和药物滥用复发方面发挥重要作用。促肾上腺皮质激素释放激素受体 (CRHR1) 在应激反应的启动中发挥着核心作用。我们发现，CRHR1 拮抗剂安塔拉明可减少急性乙醇戒断后乙醇依赖大鼠的乙醇自我给药，但不会减少乙醇非依赖大鼠的乙醇自我给药。在相关研究中，我们发现安塔拉明减轻了育亨宾应激诱导的大鼠操作性酒精自我管理的增加和酒精寻求的恢复。最后，我们发现，非依赖性撒丁岛酒精偏好大鼠的自发乙醇自我给药受到阿片拮抗剂纳曲酮的抑制，因此产生阿片类药物依赖性。 CRHR1 拮抗剂 LWH-63 减少了这些大鼠的戒断诱导饮酒，但不减少非依赖性大鼠的自发饮酒，表明阿片类药物和 CRHR1 受体在乙醇强化中发挥不同的作用。这些研究表明，CRHR1 拮抗剂可能与纳曲酮联合用于治疗人类酒精依赖，并且不同亚型患者的最佳治疗可能有所不同。 亚甲二氧基甲基苯丙胺（MDMA）和相关致幻药物的滥用是另一个严重问题。美国缉毒局的最新数据显示，出现了新型致幻苯乙胺和色胺，这些物质以前曾遇到过，数量很少，或者根本没有见过。这在一定程度上是由于最近出版了化学合成食谱，并详细说明了 A. T. Shulgin 及其同事合成和自行施用的几乎所有 179 种苯乙胺和 53 种色胺类似物的使用剂量和在人类中观察到的致幻作用。 30多年来。这些令人不安的事态发展极大地帮助和鼓励了秘密毒品生产，并可能预示着致幻药物滥用的死灰复燃。我们已经开始了一项合成和评估多种致幻剂及其拮抗剂的计划。我们开发了 5-HT2A 受体拮抗剂 MDL100,907、其用于正电子发射断层扫描的碳 11 前体及其对映体的实用非色谱化学合成方法。我们研究了其中几种药物的区别刺激作用，以便进一步了解它们的 5-HT 受体亚型选择性以及受体在某些神经精神疾病中可能的作用。我们的结果表明，5-HT2A 受体参与裸盖菇素诱导的大鼠刺激控制。该受体还被发现在 N,N-二丙基色胺的激动剂作用中发挥着重要作用，其中可能有 5-HT1A 受体的贡献。 最后，我们回顾了报告期内（a）促肾上腺皮质激素释放激素拮抗剂的潜在用途和（b）生物胺再摄取抑制剂（潜在的可卡因和甲基苯丙胺治疗剂）的结构-活性关系。

项目成果

Design and synthesis of 2- and 3-substituted-3-phenylpropyl analogs of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: role of amino, fluoro, hydroxyl, methoxyl, methyl, m

1-[2-[双(4-氟苯基)甲氧基]乙基]-4-(3-苯基丙基)哌嗪和1-[2-(二苯基甲氧基)的2-和3-取代-3-苯基丙基类似物的设计和合成

• 发表时间: 2008-05-08
• 影响因子: 7.3
• 作者: Hsin, Ling;Chang, Li;Rothman, Richard B;Dersch, Christina M;Jacobson, Arthur E;Rice, Kenner C
• 通讯作者: Rice, Kenner C

Negative inotropic and chronotropic effects of delta-opioid receptor antagonists are mediated via non-opioid receptors.

δ-阿片受体拮抗剂的负性肌力和变时作用是通过非阿片受体介导的。

• 发表时间: 2006-04
• 影响因子: 0.7
• 作者: Maslov, L N;Lishmanov, Yu B;Barzakh, E I;Lasukova, T V;Rice, K K;Oeltgen, P R
• 通讯作者: Oeltgen, P R