FLUPIRTINE GLUCONATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C15H17FN4O2.C6H12O7
Molecular Weight	500.4748
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.CCOC(=O)NC1=CC=C(NCC2=CC=C(F)C=C2)N=C1N

InChI

InChIKey=KTUKTXYTLNEYHO-IFWQJVLJSA-N

InChI=1S/C15H17FN4O2.C6H12O7/c1-2-22-15(21)19-12-7-8-13(20-14(12)17)18-9-10-3-5-11(16)6-4-10;7-1-2(8)3(9)4(10)5(11)6(12)13/h3-8H,2,9H2,1H3,(H,19,21)(H3,17,18,20);2-5,7-11H,1H2,(H,12,13)/t;2-,3-,4+,5-/m.1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20839897 | https://www.ncbi.nlm.nih.gov/pubmed/22557738

Flupirtine is a triaminopyridine derivative having a chemical structure - 2-amino-3-ethoxy-carbonylamino-6-4-fluoro-benzylamino-pyridine. The basic molecule used for synthesis of flupirtine was 2, 6-dichoro 3-nitropyridine. It was first synthesized in 1980s in Germany and was marketed by Degussa Pharma. Flupirtine is a centrally acting, non-opioid analgesic that is available in a number of European countries for the treatment of a variety of pain states. The therapeutic benefits seen with flupirtine relate to its unique pharmacological properties. Flupirtine displays indirect NDMA receptor antagonism via activation of potassium channels and is the first representative of a pharmacological class denoted the 'selective neuronal potassium channel openers'. The generation of the M-current is facilitated by flupirtine via the opening of neuronal Kv7 potassium channels. The opening of these channels inhibits exaggerated neuronal action potential generation and controls neuronal excitability. Neuronal hyperexcitability is a physiological component of many pain states such as chronic pain, migraine and neurogenic pain.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Glutamate [NMDA] receptor 125 Target ID: CHEMBL2094124 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9510072 \| https://www.ncbi.nlm.nih.gov/pubmed/10599868	Antagonist 2778
KCNQ (Kv7) potassium channel 10 Target ID: CHEMBL2363063 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20839897 \| https://www.ncbi.nlm.nih.gov/pubmed/9421279 \| https://www.ncbi.nlm.nih.gov/pubmed/23394517	Opener 34

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute (short-term) pain 4 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22557738 https://www.ncbi.nlm.nih.gov/pubmed/20839897	Primary		Approved 8429	Flupirtine Approved Use Treatment of acute pain in adults

PubMed

Title	Date	PubMed
Quantitation of flupirtine and its active acetylated metabolite by reversed-phase high-performance liquid chromatography using fluorometric detection.	1984 Jan 13	6707137
[General pharmacologic studies on the analgesic flupirtine].	1985	4039152
Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment.	1988 May	3200777
Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat.	1988 Sep	2901483
Antiparkinsonian and other motor effects of flupirtine alone and in combination with dopaminergic drugs.	1997 May 26	9185829
Melatonin counteracts ischemia-induced apoptosis in human retinal pigment epithelial cells.	1998 Nov	9804146
The therapeutic potential of neuronal KCNQ channel modulators.	2003 Dec	14640909
M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals.	2004 Jan 21	14736843
Pharmacological characterisation of acid-induced muscle allodynia in rats.	2004 Mar 8	15033380
Efficacy of flupirtine on cognitive function in patients with CJD: A double-blind study.	2004 Mar 9	15007119
Tumor-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-mediated death of neurons in living human brain tissue is inhibited by flupirtine-maleate.	2005 Oct	16043230
[The use of katadolon in patients with spondylogenic dorsalgia].	2006	17176603
[Use of katadolon in the treatment of abuse headache].	2006	17117672
[The use of katadolon (flupirtine) in the treatment of lower back pain].	2006	16737166
Retigabine and flupirtine exert neuroprotective actions in organotypic hippocampal cultures.	2006 Aug	16697426
The use of flupirtine in treatment of tinnitus.	2006 Dec	17114151
Molecular expression and pharmacological identification of a role for K(v)7 channels in murine vascular reactivity.	2007 Jul	17519950
Flupirtine attenuates sodium nitroprusside-induced damage to retinal photoreceptors, in situ.	2007 Jul 12	17562394
[Efficacy of katadolon and cranial-spine electromagnetic neuromodulation in patients with discogenic radiculopathy].	2008	19097315
Systematic review of therapeutic interventions in human prion disease.	2008 Apr 8	18391159
K(+)-channel openers suppress epileptiform activities induced by 4-aminopyridine in cultured rat hippocampal neurons.	2008 Dec	19075508
Analgesic efficacy and tolerability of flupirtine vs. tramadol in patients with subacute low back pain: a double-blind multicentre trial*.	2008 Dec	19032134
Antihyperalgesic and analgesic properties of the N-methyl-D-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia.	2008 Jan	17449306
[Analgesic and muscle tonus normalizing effect of flupirtine retard in chronic back pain. Results of a standardized therapeutic evaluation applying objective methods for measuring pain pressure threshold, pain pressure tolerance and muscle tension].	2008 Jan 17	18402240
The efficacy of tetracyclines in peripheral and intracerebral prion infection.	2008 Mar 26	18365024
G-protein inwardly rectifying potassium channels are involved in the hypotensive effect of I1-imidazoline receptor selective ligands.	2008 May	18398346
Vascular KCNQ potassium channels as novel targets for the control of mesenteric artery constriction by vasopressin, based on studies in single cells, pressurized arteries, and in vivo measurements of mesenteric vascular resistance.	2008 May	18272810
Flupirtine as neuroprotective add-on therapy in autoimmune optic neuritis.	2008 Nov	18832577
Combination therapy with flupirtine and opioid: open-label case series in the treatment of neuropathic pain associated with cancer.	2008 Oct	18950447
Combination therapy with flupirtine and opioid: studies in rat pain models.	2008 Oct	18950446
Bimodal effects of the Kv7 channel activator retigabine on vascular K+ currents.	2008 Sep	18536747
Neural KCNQ (Kv7) channels.	2009 Apr	19298256
Treatment with the Kv7 potassium channel activator flupirtine is beneficial in two independent mouse models of pulmonary hypertension.	2009 Aug	19508393
Investigation of the in vitro metabolism of the analgesic flupirtine.	2009 Mar	19074524
Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine.	2010	22291509
[New approaches to the treatment of chronic daily headache].	2010	21183903
The M-channel blocker linopirdine is an agonist of the capsaicin receptor TRPV1.	2010	21099148
[IGOST guideline for pharmacotherapy of low back pain].	2010 Aug 12	20828068
Positive reinforcing effects of flupirtine--two case reports.	2010 Aug 16	20362025
Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development.	2010 Dec	20829430
Flupirtine may stop the progressive course of subacute sclerosing panencephalitis.	2010 Dec	20702046
Enhancement of axonal potassium conductance reduces nerve hyperexcitability in an in vitro model of oxaliplatin-induced acute neuropathy.	2010 Dec	20670646
Evidence of key tinnitus-related brain regions documented by a unique combination of manganese-enhanced MRI and acoustic startle reflex testing.	2010 Dec 15	21179508
[2010 German Pain Congress. Backache - new data, specific muscle etiology and targeted therapy].	2010 Dec 16	21294372
[Musculoskeletal pain. Pain relief with muscle relaxant].	2010 Dec 2	21222334
Discrepancy between prevalence and perceived effectiveness of treatment methods in myofascial pain syndrome: results of a cross-sectional, nationwide survey.	2010 Feb 11	20149248
The Kv7 potassium channel activator flupirtine affects clinical excitability parameters of myelinated axons in isolated rat sural nerve.	2010 Mar	20433607
Green urine following exposure to flupirtine.	2010 Nov	20970027
Flupirtine in pain management: pharmacological properties and clinical use.	2010 Oct	20839897
M-type potassium channels modulate the intrinsic excitability of infralimbic neurons and regulate fear expression and extinction.	2010 Sep 15	20844133

Patents

Sample Use Guides

In Vivo Use Guide

Flupirtine can be administered by oral and rectal routes. It is available as 50 and 100 mg for oral administration. Adult dose is 300–400 mg per day and can be increased to 600 mg per day. Dose in children is 150–200 mg per day in 3–4 divided doses. Rectal suppositories are administered in the dose range of 450–600 mg per day in adults and 150–250 mg per day in children.

Route of Administration: Other

In Vitro Use Guide

Variations in the growth of U373 MG cells in 5 mM N-methyl-D-aspartate (NMDA), 1 mM flupirtine, and combined treatment indicated the antagonistic effects of NMDA and flupirtine on MG cell lines. The variation in the percentage of gated cell population in different cell cycle phases showed significant variations after 48 h of treatment.

Name

Type

Language

FLUPIRTINE GLUCONATE

Common Name

English

Flupirtine gluconate [WHO-DD]

Common Name

English

FLUPIRTINE D-GLUCONATE

Common Name

English

D-GLUCONIC ACID, COMPD. WITH ETHYL (2-AMINO-6-(((4-FLUOROPHENYL)METHYL)AMINO)-3-PYRIDINYL)CARBAMATE

Common Name

English

Code System Code Type Description

PUBCHEM

18608234