Lohocla 201(Lohocla 201) - 药物靶点：NMDA receptor x Nav1.7 x Nav1.8 x δ opioid receptor_专利_临床

概要

基本信息

药物类型

小分子化药

别名

DCUKA、Kindolor、LOHOCLA201

靶点

NMDA receptor x Nav1.7 x Nav1.8 x δ opioid receptor

作用方式

调节剂、激动剂

作用机制

NMDA receptor调节剂(谷氨酸[NMDA]受体复合体调节剂)、Nav1.7调节剂(IX型钠通道蛋白α亚基调节剂)、Nav1.8调节剂(X型钠通道蛋白α亚基调节剂)

治疗领域

神经系统疾病其他疾病

在研适应症-

非在研适应症

慢性疼痛

原研机构

Lohocla Research Corp.

在研机构-

非在研机构

Lohocla Research Corp.

权益机构-

最高研发阶段终止临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

1

项与 Lohocla 201 相关的临床试验

NCT06243835

/ Terminated临床1期

A Phase 1a Randomized, Double-blind, Placebo-controlled, Single Site, Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of Kindolor Tosylate in Healthy Adults

The goal of this study is to test Kindolor in healthy adults. The main questions it aims to answer are:
* What is the safe dose of Kindolor in healthy volunteers?
* How is Kindolor metabolized by the human body?
Participants will undergo medical tests before and after receiving Kindolor or a placebo to see if there is any difference between the groups.

开始日期2024-04-21

申办/合作机构

Lohocla Research Corp.

[+1]

100 项与 Lohocla 201 相关的临床结果

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100 项与 Lohocla 201 相关的转化医学

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100 项与 Lohocla 201 相关的专利（医药）

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3

项与 Lohocla 201 相关的文献（医药）

2026-01-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Nezavist (DCUK-OEt) and aminoquinoline analogues interact with the etomidate site and display a complex mode of modulatory action of the GABAA receptor

Article

作者: Doppler, Angelika Maria ; Tabakoff, Boris ; Scholze, Petra ; Khom, Sophia ; Ernst, Margot ; Simeone, Xenia ; Seidel, Thomas

The aminoquinoline compound Nezavist (DCUK-OEt; ethyl 5,7-dichloro-4-(3,3-diphenylureido)quinoline-2-carboxylate) is under preclinical and early clinical investigation for chronic pain, alcohol use disorder (AUD), and relapse prevention in nicotine dependence. It and its metabolite DCUKA (5,7-dichloro-4-(3,3-diphenylureido)quinoline-2-carboxylic acid) have been shown previously to be allosteric positive modulators of GABA_A receptors. Here, we investigated the two new derivatives BCUKA (5,7-dichloro-4-(3,3-dibutylureido)quinoline-2-carboxylic acid) and BCUK-OEt (ethyl 5,7-dichloro-4-(3,3-dibutylureido)quinoline-2-carboxylate) and demonstrated that all four compounds enhance GABA-induced currents more strongly in β3-than in β1-containing receptors. Moreover, the presence of γ2 impacts on modulation with compound-specific differences. Previously observed α-isoform specificity does not extend to α6, which responds as α1. Mutational analysis using β3N265S showed that the etomidate binding site contributes to the positive allosteric effects, particularly for DCUK-OEt. The mutation had less impact when γ2 was present, suggesting involvement of additional binding sites. The presence of multiple allosteric sites is supported by radioligand binding studies where DCUKA and BCUKA displaced [³H]flunitrazepam (benzodiazepine site), whereas DCUK-OEt and BCUK-OEt enhanced its binding allosterically. Docking confirmed strong interactions at the etomidate site (transmembrane β+/α- interface), with the best ranked poses of DCUK-OEt forming stabilizing hydrogen bonds and salt bridges. DCUKA and BCUKA also fit well into the high-affinity benzodiazepine site, though likely act there as silent binders. This comprehensive study demonstrates that Nezavist (DCUK-OEt) and its derivatives are multi-site GABA_A receptor modulators. Their actions depend on subunit composition and involve both known (extracellular and trans-membrane) and proposed novel allosteric sites. These findings support ongoing drug development for AUD and related conditions.

2020-01-01·Journal of psychiatry and brain science

Controlling the “Opioid Epidemic”: A Novel Chemical Entity (NCE) to Reduce or Supplant Opiate Use for Chronic Pain

Article

作者: Tabakoff, Boris ; Hoffman, Paula L

We report on the ongoing project "A Novel Therapeutic to Ameliorate Chronic Pain and Reduce Opiate Use." Over 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10% of the world's population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids and the use of opioids for pain treatment has resulted in what has been called an "epidemic" of opioid abuse, addiction and lethal overdoses. We have, through a process of rational drug design, generated a novel chemical entity (NCE) and have given it the name Kindolor. Kindolor is a non-opiate, non-addicting molecule that was developed specifically to simultaneously control the aberrant activity of three targets on the peripheral sensory system that are integral in the development and propagation of chronic pain. In our initial preclinical studies, we demonstrated the efficacy of Kindolor to reduce or eliminate chronic pain in five animal models. The overall goal of the project is to complete the investigational new drug (IND)-enabling preclinical studies of Kindolor, and once IND approval is gained, we will proceed to the clinical Phase Ia and 1b safety studies and a Phase 2a efficacy study. The work is in its second year, and the present report describes progress toward our overall goal of bringing our compound to a full Phase 2 ready stage.

2002-11-01·Experimental neurology2区 · 医学

Inhibition of Neuronal Na+ Channels by the Novel Antiepileptic Compound DCUKA: Identification of the Diphenylureido Moiety as an Inactivation Modifier

2区 · 医学

Article

作者: Boris Tabakoff ; Simon R. Levinson ; Ze-Jun Wang ; Lawrence D. Snell

In a previous analysis of existing antiseizure compounds, we suggested that a common diphenylureido moiety was responsible for the activity-dependent, Na(+) channel blocking actions of these drugs (L. D. Snell et al., 2000, J. Pharmacol. Exp. Ther. 292: 215-227). Thus the novel diphenylureido compound [N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxyquinoline] DCUKA was developed to incorporate the diphenylureido pharmacophore into a structure that also acted as an NMDA receptor antagonist. DCUKA has previously been shown to have antiepileptic properties in animals, and in the present study the actions of DCUKA on Na(+) currents were characterized using transfected cells that stably expressed the rat brain Na(v)1.2 channel isoform. In whole-cell voltage-clamp recordings, DCUKA reduced Na(+) currents in a dose- and membrane potential-dependent fashion, with an apparent 1:1 stoichiometry of drug:channel interaction. Characterization of the effects of DCUKA on Na(+) channel function strongly suggested that DCUKA acts by enhancing Na(+) channel inactivation. Thus in the presence of DCUKA, Na(v)1.2 channels showed reduced availability in steady-state inactivation protocols, displayed use-dependent inhibition, and were slower to recover from inactivation than untreated channels, while DCUKA showed no significant interaction with the open state of the channel. As previously postulated for the anticonvulsants carbamazepine and phenytoin, these results could be well explained by a model in which the drug preferentially interacts with the fast inactivated state of the channel. Finally, DCUKA was generally more efficacious than carbamazepine in modifying sodium channel behavior. Thus the diphenylureido moiety identified by a structural analysis of classic anticonvulsants appears to be important to the inactivation-specific Na(+) channel inhibition by this class of antiseizure agents.

100 项与 Lohocla 201 相关的药物交易

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