纳瓦卡普兰特是一种新型和选择性的卡帕阿片类受体对抗剂,没有与阿片类药物相关的滥用相关的激素特性
Filomene G Morrison1, Lori Jean Van Orden1, Karla Zeitz1
1Neumora Therapeutics, Inc., 490 Arsenal Way, Watertown, MA, 02472, USA.
Neuropharmacology
|June 14, 2024
概括
纳瓦卡普兰特是一种选择性的卡帕阿片类受体 (KOR) 抗剂. 这项研究证实了其KOR抗性质和缺乏激素活性,表明它有可能在没有滥用责任的情况下治疗严重抑郁症.
科学领域:
- 药理学 药理学是指药理学的学科.
- 神经科学是一个神经科学.
- 药物发现 药物发现 药物发现
背景情况:
- 卡帕阿片类受体 (KORs) 参与精神和神经疾病.
- 针对KOR系统提供了治疗潜力.
- 纳瓦卡普兰特 (NMRA-140) 是一种被研究用于重大抑郁症的KOR抗剂.
研究的目的:
- 为了进一步描述纳瓦卡普兰特的药理概况.
- 为了确认其作为KOR对手的选择性.
- 评估其缺乏对KOR和相关目标的激动性活动.
主要方法:
- 在体外测试中使用表达人类阿片类受体 (KOR,MOR,DOR) 的CHO-K1细胞.
- 在小鼠和老鼠的体内研究,包括尾巴测试和前乳素释放测量.
- 在老鼠核中评估细胞外多巴胺水平.
主要成果:
- 纳瓦卡普兰特在体外显示有选择性的KOR对抗性 (IC50 = 0.029μM) 与MOR和DOR相比.
- 在体内,纳瓦卡普兰特剂量依赖地阻断了KOR主动剂诱导的止痛,并减少了前乳素的释放.
- 纳瓦卡普兰特在任何阿片类受体亚型中都没有表现出激素活性,并且与吗啡不同,它对多巴胺水平没有影响.
结论:
- 纳瓦卡普兰特是一种强效和选择性的KOR抗剂.
- 该药物缺乏对阿片类受体的激素活性,这表明滥用潜力较低.
- 纳瓦卡普兰特的个人资料支持其用于重大抑郁症的发展.
相关概念视频
Opioid Analgesics: Synthetic and Semisynthetic Opioids
275
Synthetic and semisynthetic opioids are pivotal in pain management and tackling opioid addiction. Semisynthetic opioids, including morphinans (morphine derivatives), oxycodone, oxymorphone, hydrocodone, and hydromorphone, have improved pharmacokinetic profiles compared to morphine. Additionally, heroin and 6-MAM (6-Monoacetylmorphine) show better CNS penetration than morphine due to heightened lipid solubility. Hydromorphone, a potent opioid, undergoes hepatic metabolism to form the active...
275
Opioid Receptors: Overview
714
Opioid receptors, including the mu (μ, MOR), delta (δ, DOR), and kappa (κ, KOR) types, belong to the rhodopsin family of G protein-coupled receptors. These receptors are located throughout the central and peripheral nervous systems and in non-neuronal tissues such as macrophages and astrocytes. Opioid receptor ligands can be categorized into agonists or antagonists. Highly selective agonists include [d-Ala2, MePhe4, Gly(ol)5]-enkephalin or DAMGO for MOR, [D-Pen2,...
714
Analgesia and Pain Management
575
Pain is critical to various clinical pathologies, provoking an urgent need for effective management. Pain, whether acute or chronic, is a complex neurochemical process. Its alleviation depends on the type, with nonopioid analgesics effective for mild to moderate pain, such as musculoskeletal or inflammatory pain, while neuropathic pain responds best to anticonvulsants, tricyclic antidepressants, or serotonin/norepinephrine reuptake inhibitors. For severe acute or chronic pain, opioids may be...
575
Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists
159
Neurokinin 1 (NK1) receptors are distributed across the GI tract, vagal afferents, and key CNS regions including the central vomiting center and chemoreceptor trigger zone (CTZ) Chemotherapy agents stimulate enterochromaffin cells in the gastrointestinal (GI) tract to release large amounts of substance P (SP). SP is a neuropeptide released by specific sensory nerves in response to many different stressors, including those in the GI mucosa affected by chemotherapy. SP binds and activates...
159
Drug-Receptor Interaction: Antagonist
2.9K
An antagonist is a drug that binds strongly to a receptor without activating it. An antagonist prevents other molecules, such as neurotransmitters or hormones, from binding to the receptor and triggering a cellular response. Such interaction effectively hinders the normal physiological processes mediated by the receptor, resulting in various pharmacological effects depending on the specific receptor targeted.
Antagonists can be classified as competitive or noncompetitive based on their...
Antagonists can be classified as competitive or noncompetitive based on their...
2.9K
Opioid Analgesics: Morphine and Other Natural Cogeners
231
Opioids are a class of drugs that mimic endogenous opioid peptides and act on opioid receptors, and help in pain relief. These compounds are classified as natural, synthetic, or semi-synthetic. Natural opioids, like morphine, codeine, and thebaine, are derived from the opium poppy plant (Papaver somniferum or Papaver album) and are termed opiates. Synthetic opioids are artificial, while semi-synthetic opioids combine natural and synthetic compounds. Morphine, a prototypical opioid, possesses a...
231


