Alcohol use disorder (AUD) is a neuropsychiatric condition affecting millions of people worldwide. Topiramate (TPM) is an antiepileptic drug that has been shown to reduce ethanol drinking in humans. However, TPM is associated with a variety of adverse effects due to its interaction with many receptor systems and intracellular pathways. GluK1-containing kainate receptors (GluK1*KARs) are non-selectively inhibited by TPM, and genetic association studies suggest that this receptor system could be targeted to reduce drinking in AUD patients. We examined the efficacy of LY466195, a selective inhibitor of GluK1*KAR, in reducing ethanol consumption in the intermittent two-bottle choice paradigm in mice. The effect of LY466195 on various ethanol-related phenotypes was investigated by quantification of alcohol intake, physical signs of withdrawal, conditioned place preference (CPP) and in vivo microdialysis in the nucleus accumbens. Selective GluK1*KAR inhibition reduced ethanol intake and preference in a dose-dependent manner. LY466195 treatment attenuated the physical manifestations of ethanol withdrawal and influenced the rewarding properties of ethanol. Interestingly, LY466195 injection also normalized changes in dopamine levels in response to acute ethanol in ethanol-dependent mice, but had no effect in ethanol-naïve mice, suggesting ethanol state-dependent effects. The data point to GluK1*KARs as an attractive pharmacological target for the treatment of AUD.

01 Feb 2017·Neuroscience LettersQ4 · MEDICINE

Effects of LY466195, a selective kainate receptor antagonist, on ethanol preference and drinking in rats

Q4 · MEDICINE

Article

Author: Kranzler, Henry R ; Pierce, R Christopher ; Hernandez, Nicole S ; Van Nest, Duncan ; Schmidt, Heath D

There is evidence that variation in the gene encoding a kainate receptor subunit contributes to alcohol dependence risk. Further, there is suggestive evidence that alcohol consumption is mediated, in part, by kainate receptors. In this study, we used a novel kainate receptor antagonist, LY466195, to examine the potential role of kainate receptors in alcohol drinking behavior using a rodent model of voluntary ethanol consumption. Male Sprague Dawley and Long Evans rats were given access to 20% ethanol using the intermittent two-bottle choice paradigm. Following 6 weeks of ethanol consumption, rats were pretreated with an acute dose of LY466195 (0, 4.0 and 10.0mg/kg, i.p.) prior to a two-bottle choice test session. Acute administration of LY466195 did not significantly affect ethanol-drinking behavior in Sprague Dawley rats. In contrast, Long Evans rats pretreated with 10.0mg/kg LY466195 showed a significant reduction in alcohol preference compared to vehicle-treated controls. Decreased alcohol preference in the Long Evans rats was associated with increased water intake and no change in the amount of ethanol consumed. Taken together, these results suggest that systemic administration of a selective kainate receptor antagonist reduces ethanol preference in rats, an effect that could be due to non-specific effects on overall drinking behavior.

01 Mar 2015·PainQ1 · MEDICINE

Modulation of nociceptive dural input to the trigeminocervical complex through GluK1 kainate receptors

Q1 · MEDICINE

Article

Author: Goadsby, Peter J. ; Andreou, Anna P. ; Lasalandra, Michele P. ; Holland, Philip R.

Migraine is a common and disabling neurologic disorder, with important psychiatric comorbidities. Its pathophysiology involves activation of neurons in the trigeminocervical complex (TCC). Kainate receptors carrying the glutamate receptor subunit 5 (GluK1) are present in key brain areas involved in migraine pathophysiology. To study the influence of kainate receptors on trigeminovascular neurotransmission, we determined the presence of GluK1 receptors within the trigeminal ganglion and TCC with immunohistochemistry. We performed in vivo electrophysiologic recordings from TCC neurons and investigated whether local or systemic application of GluK1 receptor antagonists modulated trigeminovascular transmission. Microiontophoretic application of a selective GluK1 receptor antagonist, but not of a nonspecific ionotropic glutamate receptor antagonist, markedly attenuated cell firing in a subpopulation of neurons activated in response to dural stimulation, consistent with selective inhibition of postsynaptic GluK1 receptor-evoked firing seen in all recorded neurons. In contrast, trigeminovascular activation was significantly facilitated in a different neuronal population. The clinically active kainate receptor antagonist LY466195 attenuated trigeminovascular activation in all neurons. In addition, LY466195 demonstrated an N-methyl-d-aspartate receptor-mediated effect. This study demonstrates a differential role of GluK1 receptors in the TCC, antagonism of which can inhibit trigeminovascular activation through postsynaptic mechanisms. Furthermore, the data suggest a novel, possibly presynaptic, modulatory role of trigeminocervical kainate receptors in vivo. Differential activation of kainate receptors suggests unique roles for this receptor in pro- and antinociceptive mechanisms in migraine pathophysiology.

100 Deals associated with LY-466195

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Migraine Disorders	Preclinical	CA	Allelix Biopharmaceuticals, Inc.	11 May 2006
Migraine Disorders	Preclinical	US	Eli Lilly & Co.	11 May 2006

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

LY-466195

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation