Positive Allosteric Modulators (PAMS) of Strychnine-Sensitive Glycine Receptors - A New Concept in Treating Chronic Pain

士的宁敏感甘氨酸受体的正变构调节剂 (PAMS) - 治疗慢性疼痛的新概念

• 批准号: MR/J014826/1
• 负责人: Martin Leuwer
• 金额: $ 145.82万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ014826%2F1
• 关键词: Positive; Allosteric; Modulators; PAMS; Strychnine

The Problem/Background: Our project addresses the longstanding urgent, unmet medical need of chronic pain. This debilitating condition affects about 20% of adults in Europe and in the USA, i.e. more than 8 million adult patients in the UK alone, wrecking individual lives and causing huge economical damage, predominantly in terms of lost working days. One key issue is the fact that the symptomatic medication currently available is effective only in about 40% of chronic pain sufferers and even these patients struggle to maintain the balance between adequate pain relief and their ability to cope with the substantive drug-induced adverse effects. This creates a vicious cycle of insufficient analgesia and unbearable side effects ultimately leading to discontinuation of treatment. Despite these problems growth in the neuropathic pain market alone is forecasted to rise to over $6.3 billion by 2017. The Concept:As regards understanding the pathophysiology of chronic pain there is evidence that loss of inhibitory neuronal transmission within the spinal cord plays a key role. This reduced capacity to inhibit nerve activity, comparable to defective dampers inside a piano, contributes to a functional dysequilibrium state of the central nervous system referred to as central pain sensitisation. The loss involves a particular type of cell membrane-spanning protein channels operated by distinct messenger molecules, mainly glycine. Thus, enhancement of glycinergic neurotransmission should compensate for this loss. Our Proposal/Solution - A First-In-Kind Causal Treatment: Consequently, we propose to develop a novel class of compounds which do enhance glycinergic neurotransmission effectively and selectively at the spinal cord level, thereby achieving the intended effect while avoiding unwanted and dangerous side effects, e.g. deep sedation/loss of consciousness. By the end of this project we should to be ready for development into a drug that will be taken orally for a limited period of time in order to reset the proper equilibrium state of the patient's central nervous system. Our ultimate aim is allowing chronic pain patients to regain a dramatically improved quality of life.What has been achieved so far: We have successfully progressed to the discovery/synthesis of a novel class of compounds with selective enhancing effects at strychnine-sensitive glycine receptors, which do not mediate sedative effects. We are confident that this feature makes our development program highly competitive, viable and significant and have protected the Intellectual Property by filing a composition of matter patent. Moreover, we have obtained proof-of-concept for one key compound in a rat model of neuropathic pain. Work Plan: The project is currently in the hit-to-lead stage development stage, i.e., we do already know that our concept works but we need to further improve chemistry features of our compounds in preparation for our ultimate aim, i.e. generating drugs which are safe/effective and can be taken orally, e.g. 3 times/day. We plan to achieve such optimised leads within two years. Impact:In view of the huge numbers of patients worldwide whose lives are wrecked by chronic pain, the fact that current treatment options are clearly insufficient and the dramatic toll on economies caused by millions of lost working hours, it is safe to say that our first-in-kind causal treatment option has the potential to have a dramatic beneficial impact on individuals and societies.Our Solution Has Potential To Be A Platform-Technology:We are confident, that our proposal can provide a platform technology addressing further medical conditions, e.g., opioid-withdrawal, alcoholism and anxiety. Planned Route-to-Market/Exit Strategy: Two pharmaceutical companies, Grunenthal and B.Braun have confirmed their desire to collaborate with our group, and each other, in the event of a successful completion of this programme.

问题/背景：我们的项目解决了慢性疼痛长期存在的紧迫，未满足的医疗需求。这种使人衰弱的病症影响欧洲和美国约20%的成年人，即仅在英国就有800多万成年患者，破坏个人生活并造成巨大的经济损失，主要是损失工作日。一个关键问题是，目前可用的对症药物仅对约40%的慢性疼痛患者有效，即使这些患者也难以在充分缓解疼痛与科普实质性药物引起的不良反应之间保持平衡。这造成了镇痛不足和无法忍受的副作用的恶性循环，最终导致治疗中断。尽管存在这些问题，但仅神经性疼痛市场的增长预计到2017年将超过63亿美元。概念：关于理解慢性疼痛的病理生理学，有证据表明脊髓内抑制性神经元传递的丧失起着关键作用。这种抑制神经活动的能力降低，相当于钢琴内有缺陷的阻尼器，导致中枢神经系统的功能性不平衡状态，称为中枢疼痛敏感化。这种损失涉及一种特殊类型的细胞跨膜蛋白通道，该通道由不同的信使分子（主要是甘氨酸）操纵。因此，甘氨酸能神经传递的增强应该补偿这种损失。我们的提案/解决方案-同类首创的因果治疗：因此，我们建议开发一类新型化合物，可以有效且选择性地增强脊髓水平的甘氨酸能神经传递，从而达到预期效果，同时避免不必要的和危险的副作用，例如深度镇静/意识丧失。在这个项目结束时，我们应该准备好开发一种药物，这种药物将在有限的时间内口服，以重置患者中枢神经系统的适当平衡状态。我们的最终目标是让慢性疼痛患者重新获得显着改善的生活质量。迄今为止取得的成就：我们已经成功地发现/合成了一类新型化合物，对士的宁敏感的甘氨酸受体具有选择性增强作用，不介导镇静作用。我们相信，这一特点使我们的开发计划具有高度的竞争力，可行性和重要性，并通过提交物质组合专利来保护知识产权。此外，我们已经在神经性疼痛的大鼠模型中获得了一种关键化合物的概念验证。工作计划：该项目目前正处于成功引领阶段的开发阶段，即，我们确实已经知道我们的概念是可行的，但是我们需要进一步改进我们的化合物的化学特征，以准备实现我们的最终目标，即产生安全/有效并且可以口服（例如，3次/天）的药物。我们计划在两年内实现这种优化的领先优势。影响：鉴于全球有大量患者的生活被慢性疼痛所破坏，目前的治疗方案显然不足，以及数百万工作时间损失对经济造成的巨大损失，可以肯定地说，我们的第一种因果治疗方案有可能对个人和社会产生巨大的有益影响。我们的解决方案有潜力成为一个平台技术：我们有信心，我们的建议可以提供一个平台技术，解决进一步的医疗条件，例如，阿片类药物戒断，酗酒和焦虑计划的上市路线/退出策略：两家制药公司Grunenthal和B.Braun已经确认，如果成功完成该计划，他们希望与我们集团合作，并相互合作。

项目成果

4-Chloropropofol enhances chloride currents in human hyperekplexic and artificial mutated glycine receptors.

• DOI: 10.1186/1471-2377-12-104
• 发表时间: 2012-09-24
• 期刊: BMC neurology
• 影响因子: 2.6
• 作者: de la Roche J;Leuwer M;Krampfl K;Haeseler G;Dengler R;Buchholz V;Ahrens J
• 通讯作者: Ahrens J

4-bromopropofol decreases action potential generation in spinal neurons by inducing a glycine receptor-mediated tonic conductance.

4-bromopropofol 通过诱导甘氨酸受体介导的强直电导来减少脊髓神经元动作电位的产生。

• DOI: 10.1111/bph.12880
• 发表时间: 2014
• 期刊: British journal of pharmacology
• 影响因子: 7.3
• 作者: Eckle VS