Novel 5-HT7 Antagonists for the Treatment of Pruritus

用于治疗瘙痒的新型 5-HT7 拮抗剂

基本信息

批准号：
10547410
负责人：
Carlos A Barrero
金额：
$ 27.55万
依托单位：
PRAEVENTIX, LLC
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547410
关键词：
ANK1 gene Ablation Acute Affect Afferent Neurons Agonist Alternative Therapies Atopic Dermatitis Attention Attenuated Behavior Biological Biological Assay Calcium Cells Cheek structure Chronic Concentration Camps Control Groups Coupled Cutaneous Cyclic AMP Data Dermal Dermatologic Dermatology Development Disease Dose Drug Kinetics Eczema Esthesia Ethanol Evaluation Formulation Frequencies G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Genetic In Vitro Injections Ion Channel Knockout Mice Lead Life Measures Mediating Modeling Mus Neurons Pathogenesis Pathway interactions Patients Penetration Peripheral Permeability Pharmacology Play Propylene Glycols Proteins Pruritus Reporter Reporting Rodent Role Series Serotonergic System Serotonin Severities Signal Transduction Site Skin Surface Symptoms System TRPA channel Testing Topical application alternative treatment antagonist associated symptom chronic itch drug disposition effective therapy efficacy study in vivo intradermal injection mouse model novel novel lead compound receptor release of sequestered calcium ion into cytoplasm scale up screening serotonin 7 receptor skin lesion theories

项目摘要

Project Summary (Abstract) Evidence supporting serotonin (5-HT) as a contributing factor to the severity of pruritus has been widely reported. Elevated levels of 5-HT have been reported in patients with atopic dermatitis and chronic eczema, thus supporting 5-HT as a contributing factor. Additionally, 5-HT invokes dose-dependent scratching when administered via intradermal injection in rodents. Studies have demonstrated that 5-HT induces scratching sensations by activating a subset of receptors. Substantial evidence supports a role of peripheral 5-HT7 receptors in chronic itch via opening of the TRPA1 channel. Opening of the TRPA1 channel is reported to be required for the manifestation of chronic pruritus. 5-HT7 is co-expressed with TRPA1 in a subset of primary afferent sensory neurons that innervate the skin. When 5-HT7 was activated with either 5-HT or a highly selective 5-HT7 agonist (LP-44) it triggers neuronal excitation via calcium flux thru the TRPA1 channel in a cyclic AMP dependent matter. The involvement of 5-HT7 in pruritus was supported in vivo as intradermal administration of LP-44 into the cheek of mice evoked significant scratching behavior that was attenuated via pharmacological blockade with a selective 5-HT7 antagonist (SB-269970). 5-HT and LP-44 induced scratching was also attenuated in either 5-HT7 or TRPA1 knock-out mice. Additionally, 5-HT7 and TRPA1 knock-out mice displayed reduced scratching and skin lesion severity in an atopic dermatitis model (MC903 induced) where 5-HT levels were significantly increased at the affected site. This data suggests that a 5-HT7 antagonist could be useful for the treatment of pruritus. We have chosen 6 highly potent, selective 5-HT7 antagonists that display peripherally restricted pharmacokinetic (PK), good dermal penetration/permeability and safe preliminary ADMET profiles. We hypothesize that our novel 5-HT7 antagonists will attenuate scratching in murine models of pruritus (MC903) and provide a novel mechanism for treating pruritus. We will pursue a multipronged approach focused on identifying novel lead compounds suitable for advanced in vivo efficacy studies.

项目概要（摘要）广泛报道的证据表明，血清素 (5-HT) 是导致瘙痒严重程度的一个因素。据报道，特应性皮炎和慢性湿疹患者的 5-HT 水平升高，因此支持 5-HT 作为影响因素。此外，5-HT 在以下情况下会引起剂量依赖性的抓挠：通过啮齿动物皮内注射给药。研究表明5-HT会引起抓伤通过激活一部分受体来产生感觉。大量证据支持外周 5-HT7 受体的作用通过打开 TRPA1 通道来缓解慢性瘙痒。据报道，需要打开 TRPA1 通道慢性瘙痒的表现。 5-HT7 在初级传入感觉的子集中与 TRPA1 共表达支配皮肤的神经元。当 5-HT7 用 5-HT 或高选择性 5-HT7 激动剂激活时 (LP-44) 它通过循环 AMP 依赖性物质中的 TRPA1 通道的钙通量触发神经元兴奋。通过将 LP-44 皮内注射到脸颊，在体内证实了 5-HT7 与瘙痒有关的小鼠诱发了明显的抓挠行为，这种行为可以通过选择性药物阻断来减弱 5-HT7 拮抗剂 (SB-269970)。 5-HT 和 LP-44 诱导的抓挠在 5-HT7 或 TRPA1 基因敲除小鼠。此外，5-HT7 和 TRPA1 敲除小鼠表现出抓挠和皮肤减少特应性皮炎模型（MC903 诱导）中的病变严重程度，其中 5-HT 水平显着增加受影响的站点。该数据表明 5-HT7 拮抗剂可用于治疗瘙痒。我们选择了 6 种高效、选择性 5-HT7 拮抗剂，这些拮抗剂显示出外周限制性药代动力学 (PK)、良好的皮肤渗透性/渗透性和安全的初步 ADMET 曲线。我们假设我们的新型 5-HT7 拮抗剂将减轻瘙痒小鼠模型 (MC903) 中的抓挠，并且提供了治疗瘙痒的新机制。我们将采取多管齐下的方法，重点是确定适用于高级体内功效研究的新型先导化合物。