Discovery and development of novel glycine transporter-2 inhibitors for the treatment of neuropathic pain

发现和开发用于治疗神经性疼痛的新型甘氨酸转运蛋白 2 抑制剂

• 批准号: 10592522
• 负责人: Christopher L. Cioffi
• 金额: $ 45.52万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592522
• 关键词: Absence of pain sensation; Acute Pain; Adult; Adverse effects; Analgesics; Animal Model; Behavioral Model; Benchmarking; Binding; Biological Assay; Brain; Characteristics; Clinical Trials; Collection; Data; Development; Disinhibition; Dissociation; Dose; Dose-Limiting; Equilibrium; Exhibits; Formalin Tests; GLYT2; General Population; Glycine; Healthcare; Human; Impairment; In Vitro; Libraries; Ligation; Lipids; Lysine; Malignant Bone Neoplasm; Measures; Medical; Metabolic; Metabolism; Modeling; Morphine; Morphine Abuse; Motor; Mus; Nerve; Neuropathy; Nociception; Nociceptors; Oral; Pain; Pathologic; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiology; Play; Property; Protocols documentation; Rattus; Recovery; Reflex action; Reporting; Reproducibility; Risk; Rodent Model; Role; Safety; Signal Transduction; Slice; Small Interfering RNA; Spinal; Spinal Cord; Synapses; Therapeutic Index; Tissues; Variant; absorption; abuse liability; analog; base; chronic neuropathic pain; chronic pain; cost; counterscreen; design; dorsal horn; economic cost; extracellular; improved; in vivo; inhibitor; knock-down; lead optimization; meetings; motor behavior; neurotransmission; novel; opioid sparing; pain behavior; pain model; pain reduction; pain relief; painful neuropathy; pre-clinical; presynaptic; productivity loss; side effect

It is estimated that 7–10% of the general population suffers from chronic neuropathic pain and associated annual economic costs exceed $160 billion in the US. Current analgesics used to treat chronic neuropathic pain lack efficacy, induce dose-limiting side effects or present a significant risk of tolerance and abuse. Thus, the discovery of novel analgesics that provide meaningful pain relief with improved safety, tolerability and reduced abuse potential remains an unmet medical need. Among the various mechanisms involved in pathological pain, disinhibition of nociceptive signaling from the spinal cord to the higher CNS plays a critical role. Indeed, we and others have shown that inhibitory glycinergic neurotransmission in the dorsal horn is impaired in pathological pain states. Thus, it has been proposed that enhancing spinal glycinergic neurotransmission could reduce nociceptor signaling and provide analgesia. Glycine transporter-2 (GlyT-2) regulates extracellular glycine concentrations in the CNS and presents a highly attractive target to augment impaired spinal inhibitory signaling. Indeed, GlyT-2 inhibitors have demonstrated efficacy in several rodent models of acute and chronic pain. Recent studies suggest that either partial or reversible GlyT-2 inhibition can potentially circumvent potential mechanism-based adverse effects and provide analgesics with a suitable balance of efficacy and tolerability. We synthesized 60 bioactive lipid allosteric partial inhibitors exhibiting varying degrees of potency and %maximal inhibition and our most potent compound of this class enhances tonic glycinergic currents ex vivo in rat spinal cord slices without depleting presynaptic glycine reloading and produces in vivo dose-dependent efficacy in PNL rats without adverse effects. Separately, we synthesized 18 novel GlyT-2 inhibitor hit compounds derived from ORG-25543 that exhibit reproducible variations in reversibility and transport recovery using a washout assay protocol. From these two libraries, we propose conducting a dual-pronged medicinal chemistry campaign to identify optimized compounds possessing favorable potency, binding profiles and ADME characteristics suitable for measuring effects in spinal cord slices and in vivo PK. Selected compounds will be screened in the rat PNL model to assess analgesic efficacy and in behavioral models for dose-limiting effects and TI. Our proposal seeks support to optimize our hit compounds to provide selective and orally bioavailable GlyT-2 inhibitors for further development and eventual human clinical trials in neuropathic pain. The studies outlined in this proposal seek to conduct medicinal chemistry optimization using a battery of primary, secondary, counter-screen, and ADMET assays to assess potency, binding profile (%maximal inhibition, reversibility and mechanism of binding), selectivity and drug- like properties (Specific Aim 1), and assess PK, preclinical analgesic efficacy and tolerability of advanced compounds in animal models of neuropathic pain and motor behavior at different stages of compound optimization (Specific Aim 2).

据估计，总人口中有7-10%的人患有慢性神经性疼痛及相关疾病

项目成果

Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling.

• DOI: 10.3390/biom11060864
• 发表时间: 2021-06-10
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Cioffi CL

Glycine Transporter 2: Mechanism and Allosteric Modulation.

• DOI: 10.3389/fmolb.2021.734427
• 发表时间: 2021
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Frangos ZJ;Cantwell Chater RP;Vandenberg RJ
• 通讯作者: Vandenberg RJ

Opioid overdose and tolerance: is the recruitment of β-arrestin to the µ-receptor involved?

阿片类药物过量和耐受性：是否涉及β-抑制蛋白向μ-受体的募集？

• DOI: 10.1038/s41386-021-01121-3
• 发表时间: 2021
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Gillis,Alexander;Christie,MacdonaldJ
• 通讯作者: Christie,MacdonaldJ