Delving into the Latest Updates on Flindokalner with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Flindokalner (USAN/INN)

+ [1]

Target

BK channel

Mechanism

BK channel agonists(Calcium-activated potassium channel alpha/beta 1 agonists)

Therapeutic Areas

Nervous System DiseasesCardiovascular Diseases

Active Indication-

Inactive Indication

Stroke

Originator Organization

Bristol Myers Squibb Co.

Active Organization-

Inactive Organization

Bristol Myers Squibb Co.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC16H10ClF4NO2

InChIKeyULYONBAOIMCNEH-HNNXBMFYSA-N

CAS Registry187523-35-9

It is not previously investigated whether, there is a correlation between potassium channels and migraine, so it is unclear whether, this signaling pathway through potassium channels has an impact on migraine pathophysiology.
Maxipost (BMS 204352) is a vasoactive molecule that causes vasodilation via the big calcium dependent potassium (BKCa) channel signaling pathway. Maxipost decreases the blood pressure and maxipost infusion causes headache in healthy volunteers. A possible coherence between maxipost and headache/migraine in healthy volunteers and migraine patients is yet to be investigated.
The present study aims to clarify a possible coherence between maxipost and headache/migraine and it will help to shed light on the importance of potassium channels in migraine. In general, the study will contribute to a greater understanding of migraine pathogenesis and possibly lead to development of specific migraine treatment.

Start Date01 Apr 2019

Sponsor / Collaborator

Danish Headache Center

100 Clinical Results associated with Flindokalner

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100 Translational Medicine associated with Flindokalner

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100 Patents (Medical) associated with Flindokalner

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52

Literatures (Medical) associated with Flindokalner

01 Feb 2024·Molecular Psychiatry

Ethanol’s interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice

Article

Author: Roberts, Amanda J ; Bajo, Michal ; Fleck, Kiera ; Homanics, Gregg E ; Gandhi, Pauravi J ; Contet, Candice ; Lopez, Catherine ; Kreifeldt, Max ; Martinez, Briana ; Bhattacharyya, Pushpita ; Okhuarobo, Agbonlahor ; Dopico, Alex M ; Roberto, Marisa

AbstractLarge conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. To address this question, we first tested the effect of systemically administered BK channel modulators on voluntary alcohol consumption in C57BL/6J males. Penitrem A (blocker) exerted dose-dependent effects on moderate alcohol intake, while paxilline (blocker) and BMS-204352 (opener) were ineffective. Because pharmacological manipulations are inherently limited by non-specific effects, we then sought to investigate the behavioral relevance of ethanol’s direct interaction with BK α by introducing in the mouse genome a point mutation known to render BK channels insensitive to ethanol while preserving their physiological function. The BK α K361N substitution prevented ethanol from reducing spike threshold in medial habenula neurons. However, it did not alter acute responses to ethanol in vivo, including ataxia, sedation, hypothermia, analgesia, and conditioned place preference. Furthermore, the mutation did not have reproducible effects on alcohol consumption in limited, continuous, or intermittent access home cage two-bottle choice paradigms conducted in both males and females. Notably, in contrast to previous observations made in mice missing BK channel auxiliary β subunits, the BK α K361N substitution had no significant impact on ethanol intake escalation induced by chronic intermittent alcohol vapor inhalation. It also did not affect the metabolic and locomotor consequences of chronic alcohol exposure. Altogether, these data suggest that the direct interaction of ethanol with BK α does not mediate the alcohol-related phenotypes examined here in mice.

01 May 2023·eneuro

A Targeted, Low-Throughput Compound Screen in aDrosophilaModel of Neurofibromatosis Type 1 Identifies Simvastatin and BMS-204352 as Potential Therapies for Autism Spectrum Disorder (ASD)

Article

Author: Garg, Shruti ; Baines, Richard A ; Dyson, Alex ; Ryan, Megan ; Evans, D Gareth

AbstractAutism spectrum disorder (ASD) is a common neurodevelopmental condition for which there are no pharmacological therapies that effectively target its core symptomatology. Animal models of syndromic forms of ASD, such as neurofibromatosis type 1, may be of use in screening for such treatments.Drosophilalarvae lackingNf1expression exhibit tactile hypersensitivity following mechanical stimulation, proposed to mirror the sensory sensitivity issues comprising part of the ASD diagnostic criteria. Such behavior is associated with synaptic dysfunction at the neuromuscular junction (NMJ). Both phenotypes may thus provide tractable outputs with which to screen for potential ASD therapies. In this study, we demonstrate that, while loss ofNf1expression within the embryo is sufficient to impair NMJ synaptic transmission in the larva, constitutiveNf1knock-down is required to induce tactile hypersensitivity, suggesting that a compound must be administered throughout development to rescue this behavior. With such a feeding regime, we identify two compounds from a targeted, low-throughput screen that significantly and consistently reduce, but do not fully rescue, tactile hypersensitivity inNf1P1larvae. These are the HMG CoA-reductase inhibitor simvastatin, and the BKCachannel activator BMS-204352. At the NMJ, both compounds induce a significant reduction in the enhanced spontaneous transmission frequency ofNf1P1larvae, though again not to the level of vehicle-treated controls. However, both compounds fully rescue the increased quantal size ofNf1P1mutants, with simvastatin also fully rescuing their reduced quantal content. Thus, the further study of both compounds as potential ASD interventions is warranted.

01 Nov 2022·Basic & Clinical Pharmacology & Toxicology

The role of high‐conductance calcium‐activated potassium channel in headache and migraine pathophysiology

Review

Author: Al‐Karagholi, Mohammad Al‐Mahdi ; Hakbilen, Cemile Ceren ; Ashina, Messoud

AbstractMigraine is a common, neurovascular headache disorder with a complex molecular interplay. The involvement of ion channels in the pathogenesis of migraine gathered considerable attention with the findings that different ion channels subfamilies are expressed in trigeminovascular system, the physiological substrate of migraine pain, and several ion channel openers investigated in clinical trials with diverse primary endpoints caused headache as a frequent side effect. High‐conductance (big) calcium‐activated potassium (BKCa) channel is expressed in the cranial arteries and the trigeminal pain pathway. Recent clinical research revealed that infusion of BKCa channel opener MaxiPost caused vasodilation, headache and migraine attack. Thus, BKCa channel is involved in pathophysiological mechanisms underlying headache and migraine, and targeting BKCa channel presents a new potential strategy for migraine treatment.

100 Deals associated with Flindokalner

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