Unique Opioid Analgesics With No Addiction Liability or Dysphoria

描述（由申请人提供）： 该I期申请要求资金支持新型阿片类镇痛药PPL-103的持续临床前评估，以及一系列新类似物的合成和初步临床前评估。PPL-103是一种强效镇痛药，已由Phoenix PharmaLabs，Inc.进行了早期临床前研究。(PPL)，申请组织和NIDA。PPL-103是PPL开发的尖端镇痛技术的产物。它是1979年发现的开创性但非专利化合物PPL-101的第二代类似物。这两种镇痛药在动物中均显示出低成瘾倾向和烦躁不安。因此，它们代表了治疗所有疼痛综合征（包括神经性疼痛）的一个可能的重大进展。PPL-101和PPL-103分别来自吗啡和左啡烷，因此它们在化学上类似于数百种古老的吗啡类药物。然而，它们还含有手性N-取代基，这赋予它们在μ、δ和κ阿片受体上具有高结合亲和力和部分激动剂活性的独特组合，导致与所有常规阿片类药物相比具有上级体内药理学。PPL-101强效镇痛，对胃肠道转运、呼吸、身体依赖和利尿的影响极小。PPL-103是一种较新的类似物，是一种更有效的镇痛剂，具有明显更低的成瘾倾向。此外，虽然这两种化合物本质上都是非成瘾性的，但它们在依赖动物中成功地替代了吗啡，而不会引起戒断。因此，PPL不仅发现了一类具有明显理想性质的新阿片类药物，而且还发现了赋予这些性质的独特受体活性谱。这些拟定的I期研究旨在（a）继续评价PPL-103的低成瘾性和（B）生产含有不同手性取代的其他PPL-103类似物，并在一系列体外试验和体内试验中对其进行表征。这些测试将包括：受体结合、功能药理学、甩尾和热板镇痛、作用持续时间和成瘾倾向[使用条件性位置偏好（CPP）和药物自我给药模型]。该计划将推进PPL早期的发现和理解，扩大技术管道，并提供关于独特受体谱的新见解，从而使PPL能够确定所需的阿片受体谱以及它如何导致非成瘾性，低副作用镇痛，无烦躁不安。具有独特、“平衡”阿片受体活性的新型镇痛药可以治疗许多疼痛综合征，包括神经性疼痛，副作用有限，并且没有身体依赖性。此类化合物的上级特征可以通过剂量递增实现神经性疼痛的改善结果，这对于当前的阿片类药物是不可能的。 公共卫生相关性： 阿片类药物仍然是急性和慢性疼痛最有效和最广泛使用的治疗方法。然而，与吗啡和其他标准阿片类镇痛药相关的问题已得到很好的表征。它们的使用通常会导致便秘，长期使用会导致身体和心理依赖，过量使用会导致呼吸抑制和死亡。该项目旨在发现具有独特的、“平衡的”阿片受体活性的新型镇痛药，作为传统阿片类药物的首选替代品。此类化合物可允许治疗许多疼痛综合征，包括神经性疼痛，副作用有限且无身体依赖性。这样的化合物可以（a）代替或跟随当前阿片类药物用于治疗急性和慢性背部疼痛、癌症和手术疼痛，和（B）与非阿片类镇痛剂组合用于治疗神经性疼痛、急性和慢性炎性疼痛和偏头痛，由于副作用和/或功效问题，这些疼痛在很大程度上超出了常规阿片类药物方案。我们的化合物的上级特征可以通过剂量递增实现神经性疼痛的改善结果，这对于当前的阿片类药物是不可能的。

DESCRIPTION (provided by applicant): This Phase I application requests funds to support the continued preclinical evaluation of a novel opioid analgesic, PPL-103, and the synthesis and initial preclinical evaluation of a series of new analogs thereof. PPL-103, a potent analgesic, has undergone early preclinical studies by Phoenix PharmaLabs, Inc. (PPL), the applicant organization, and NIDA. PPL-103 is the product of a cutting-edge analgesic technology being developed by PPL. It is a second-generation analog of a seminal but off-patent compound, PPL-101, discovered in 1979. Both analgesics show low addiction liability and dysphoria in animals. Thus, they represent a possible major advance in the treatment of all pain syndromes, including neuropathic pain. PPL-101 and -103 are derived from morphine and levorphanol, respectively, so they chemically resemble hundreds of old, morphine-like drugs. However, they also contain a chiral N-substituent, which confers them with unique combinations of high binding affinities and partial agonist activities at mu, delta, and kappa opioid receptors, leading to superior in vivo pharmacology compared to all conventional opioids. PPL-101 elicits potent analgesia with minimal effects on gastrointestinal transit, respiration, physical dependence, and diuresis. PPL-103, a newer analog, is an even more potent analgesic with apparently less addiction liability. Moreover, though both compounds are intrinsically non-addictive, they successfully substitute for morphine in dependent animals without precipitating withdrawal. Thus, PPL has discovered not only a new class of opioid with apparently ideal properties but also a unique receptor activity profile that confers such properties. These proposed Phase I studies aim (a) to continue evaluating the low addiction properties of PPL-103 and (b) to produce additional PPL-103 analogs containing varied chiral substitutions and to characterize them in a battery of in vitro tests and in vivo tests. Such tests will include: receptor binding, functional pharmacology, tail- flick and hot-plate analgesia, duration of action, and addiction liability [using Conditioned Place Preference (CPP) and Drug Self-Administration models]. This program will advance upon earlier discoveries and understandings gained by PPL, expand the technology pipeline, and provide new insights on a unique receptor profile, thus allowing PPL to pinpoint a desired opioid receptor profile and how it leads to non-addicting, low side-effect analgesia that is free of dysphoria. New analgesics with unique, "balanced" opioid receptor activities could permit the treatment of many pain syndromes, including neuropathic pain, with limited side effects and no physical dependence. The superior profile of such compounds could achieve improved outcomes in neuropathic pain via dose escalation, which is not possible with current opioids. PUBLIC HEALTH RELEVANCE: Opioids are still the most effective and widely used treatments for acute and chronic pain. However, the problems associated with morphine and other standard opioid analgesics are well characterized. Their use is routinely constipating, their chronic use leads to physical and psychological dependence, and their overdose leads to respiratory depression and death. This project aims to discover new analgesics with unique, "balanced" opioid receptor activities as preferred alternatives to conventional opioids. Such compounds could permit the treatment of many pain syndromes, including neuropathic pain, with limited side effects and no physical dependence. Such compounds could be positioned (a) in place of or following current opioids for treating acute and chronic back, cancer, and surgical pain, and (b) in combination with non-opioid analgesics, for treating neuropathic, acute and chronic inflammatory, and migraine pain, which are largely beyond conventional opiate regimens, due to side-effect and/or efficacy issues. The superior profile of our compounds could achieve improved outcomes in neuropathic pain via dose escalation, which is not possible with current opioids.