KCa2 Channel Activators for Opioid Use Disorder

用于治疗阿片类药物使用障碍的 KCa2 通道激活剂

基本信息

批准号：
10511349
负责人：
HEIKE WULFF
金额：
$ 41.99万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10511349
关键词：
Abstinence Acute Pain Address Affect Affinity Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome American Apamin Behavior Binding Brain Brain region Calcium-Activated Potassium Channel Calmodulin Cessation of life Chemicals Classification Clinical Cryoelectron Microscopy Crystallization Data Development Disease Docking Drug Design Drug usage Electrophysiology (science)Experimental Models FDA approved Funding Opportunities Goals Helping to End Addiction Long-term Homology Modeling Human Individual Injections Ion Channel Laboratories Length Libraries Ligands Machine Learning Methods Modeling Modification Molecular Morphine Dependence Mus Mutagenesis Neurons Nucleus Accumbens Opiate Addiction Opioid Overdose Pain Penetration Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Play Post-Traumatic Stress Disorders Prevention Publishing Rattus Rodent Rodent Model Role Running Structure Substance Addiction Substance Use Disorder Techniques Testing Therapeutic Therapeutic Agents Validation Ventilatory Depression alcohol seeking behavior base benzothiazole chronic pain comorbidity convolutional neural network craving design experience high throughput screening improved innovation insight novel novel therapeutics opioid misuse opioid therapy opioid use disorder pharmacophore polysubstance use prescription opioid prevent protein complex response screening substance use treatment virtual virtual model virtual screening

项目摘要

Abstract Both human and rodent data showing reduced expression of the small-conductance, calcium- activated potassium channel KCa2.2 (SK2) in the context of morphine and alcohol dependence and withdrawal suggest KCa2 channel activation as a promising therapeutic approach for the treatment of substance use disorders and associated comorbidities. In support of this therapeutic hypothesis, KCa2 channel activators reduce alcohol seeking and intake in rats, while direct injection of the KCa2 channel blocking peptide apamin into the nucleus accumbens, a brain region which plays a crucial role in regulating craving and drug seeking during abstinence, increases alcohol intake in mice. In response to the HEAL Initiative RFA-DA-22-032 Funding Opportunity Announcement, we are here proposing to perform virtual high-throughput-screening with the goal of identifying novel KCa2 activator pharmacophores that are free of the liabilities of the existing unselective benzothiazole-type activators and that could be developed into innovative treatments for opioid use disorders (OUD), a condition that affects more than 3 million Americans. For the implementation of this project, we will draw on our 20 years of experience with the medicinal chemistry of KCa channels. After we initially developed KCa3.1 blockers such as TRAM-34, we later discovered the mixed KCa2/3 activator SKA-31, and the KCa3.1 selective activators SKA-121 and SKA-111. All these compounds, which have been widely used in the field to probe the physiological and pathophysiological roles of KCa channels were designed using classical medicinal chemistry approaches without any structural insight. However, the MacKinnon laboratory recently published the full-length cryo-EM structure of a KCa channel in the closed and two open states and we now have a high-quality structural template available to virtually screen for novel KCa2.2 channel modulators that could be used as pharmacological probes and as leads for the design of drugs for the treatment of OUD. In Aim-1, we will validate our KCa3.1-based KCa2.2 homology model by virtually screening 2000 FDA-approved compounds in two activator binding pockets and experimentally confirm the hits by electrophysiology and mutagenesis. In Aim-2, we will perform a virtual High Throughput Screen (vHTS) of a larger, 130,000-compound library with machine learning (ML) techniques for pose classification and binding affinity prediction. Taken together, these two aims have the potential of 1) identifying a clinically used drug that could be repurposed for OUD and 2) discovering novel KCa2.2 activator pharmacophores that could serve as templates for structure- based-medicinal chemistry optimization aimed at developing OUD treatments with a novel mechanism of action.

抽象的人类和啮齿动物数据均显示小电导、钙- 在吗啡和酒精依赖的情况下激活钾通道 KCa2.2 (SK2) 和戒断表明 KCa2 通道激活是一种有前途的治疗方法物质使用障碍和相关合并症。为了支持这一治疗假设，KCa2 通道激活剂减少大鼠的酒精寻求和摄入，同时直接注射 KCa2 通道阻断肽 apamin 进入伏隔核，这是一个在大脑中起着至关重要作用的区域调节禁欲期间的渴望和药物寻求，增加小鼠的酒精摄入量。作为回应根据 HEAL Initiative RFA-DA-22-032 资助机会公告，我们在此提议进行虚拟高通量筛选，目标是识别新型 KCa2 激活剂药效团不受现有非选择性苯并噻唑类激活剂的影响这可以开发成阿片类药物使用障碍 (OUD) 的创新疗法，阿片类药物使用障碍是一种疾病这影响了超过 300 万美国人。为了实施这个项目，我们将借鉴我们20年的经验 KCa 通道的药物化学。我们最初开发了 TRAM-34 等 KCa3.1 阻断剂后，后来我们发现了混合 KCa2/3 激活剂 SKA-31 和 KCa3.1 选择性激活剂 SKA-121 和SKA-111。所有这些化合物已广泛应用于现场探测 KCa 通道的生理和病理生理作用是利用经典医学设计的化学方法没有任何结构洞察力。然而，麦金农实验室最近发表了 KCa 通道在关闭和两种打开状态下的全长冷冻电镜结构，我们现在有一个高质量的结构模板可用于虚拟筛选新颖的 KCa2.2 通道调节剂可用作药理学探针和药物设计的先导 OUD 的治疗。在 Aim-1 中，我们将通过虚拟方式验证基于 KCa3.1 的 KCa2.2 同源模型在两个激活剂结合口袋中筛选 2000 种 FDA 批准的化合物并进行实验通过电生理学和诱变确认命中。在 Aim-2 中，我们将进行虚拟高通过机器学习 (ML) 对包含 130,000 种化合物的大型库进行吞吐量筛选 (vHTS) 用于姿势分类和结合亲和力预测的技术。综合起来，这两个目标 1) 确定一种可重新用于 OUD 的临床使用药物的潜力，以及 2) 发现新的 KCa2.2 激活剂药效团，可以作为结构模板基于药物化学优化，旨在开发新型 OUD 治疗方法作用机制。