Novel 5-HT7 Antagonists for the Treatment of Pruritus

用于治疗瘙痒的新型 5-HT7 拮抗剂

• 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
• 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; 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

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.

项目摘要（摘要） 支持5-羟色胺（5-HT）作为瘙痒严重程度的一个证据已得到广泛报道。 在特应性皮炎和慢性湿疹的患者中，已经报道了5-HT水平升高，因此 支持5-HT作为促成因素。此外，当5-HT调用剂量依赖性划痕时 通过啮齿动物的皮内注射给药。研究表明5-HT引起刮擦 通过激活受体的子集来感觉。大量证据支持外围5-HT7受体的作用 在慢性瘙痒中通过打开TRPA1通道。据报道，需要开放TRPA1通道 慢性瘙痒的表现。 5-HT7与TRPA1共表达在主要传播感觉的子集中 神经支配皮肤的神经元。当5-HT或高度选择性5-HT7激动剂激活5-HT7时 （LP-44）它通过循环AMP依赖性物质中的TRPA1通道通过钙通道触发神经元激发。 5-HT7参与瘙痒，在体内支持LP-44的皮内给药 小鼠唤起了明显的刮擦行为，这些行为通过药理学封锁而减弱了 5-HT7拮抗剂（SB-269970）。在5-HT7或 TRPA1敲除小鼠。此外，5-HT7和TRPA1敲除小鼠的划痕和皮肤减少 特应性皮炎模型中的病变严重程度（MC903诱导），其中5-HT水平显着增加 受影响的网站。该数据表明，5-HT7拮抗剂可能对治疗瘙痒有用。我们 选择了6个高效，有选择性的5-HT7拮抗剂，这些拮抗剂显示外周限制 药代动力学（PK），良好的皮肤渗透/渗透性和安全的初步药物剖面。我们 假设我们的新颖的5-HT7拮抗剂将减弱瘙痒模型（MC903）和 提供了一种新的治疗瘙痒的机制。我们将采用一种多管齐下的方法，专注于识别 新型铅化合物适用于晚期体内功效研究。