Flupirtine, a re-discovered drug, revisited

Abstract

Flupirtine was developed long before K(V)7 (KCNQ) channels were known. However, it was clear from the beginning that flupirtine is neither an opioid nor a nonsteroidal anti-inflammatory analgesic. Its unique muscle relaxing activity was discovered by serendipity. In the meantime, broad and intensive research has resulted in a partial clarification of its mode of action. Flupirtine is the first therapeutically used K(V)7 channel activator with additional GABA(A)ergic mechanisms and thus the first representative of a novel class of analgesics. The presently accepted main mode of its action, potassium K(V)7 (KCNQ) channel activation, opens a series of further therapeutic possibilities. One of them has now been realized: its back-up compound, the bioisostere retigabine, has been approved for the treatment of epilepsy.

TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms

“…The mechanism of flupirtine action is thought to be based on the drug's ability to open voltage gated potassium channels in the central nervous system [69]. Administration of flupirtine has been associated with hepatocellular injury and is thought to be related to flupirtine metabolism, which has previously been shown to undergo both oxidative and conjugative reactions in vivo and in vitro [70–72].…”

Cu-Catalyzed Expeditious Synthesis of N-Benzylaminoheter-ocycles Using N-Tosylhydrazones and Aminoheteroarenes

“…[24] Recently, Cui's group reported the synthesis of Nvinylindoles involving Pd-catalyzed reaction of N-tosylhydrazones with indoles. [25] Recently, Abdallah Hamze and his group reported the coupling of N-tosylhydrazones, mainly with secondary aliphatic amines and a few examples of primary amines using Cu(acac) 2 and Cs 2 CO 3 in dioxane at 100 o C for 3 h. However, under these conditions benzylation of arylamine (anisidine) using N-tosylhydrazone of acetophenone failed to deliver the corresponding N-benzylated product and generated a styrene derivative.…”

“…[1] In recent past, various N-benzylaminoheterocycles such as Flupirtine, [2] Ferroquine, [3] aminothiazole derivative, [4] IMC-094332, [5] Tripelennamine [6] have been emerged as drug candidates (Figure 1). Besides medicinal uses, some of the Nbenzylamino-heterocycles have been proved to exhibit prominent applications in materials science.…”

Oxidation Potentials of N‐Modified Derivatives of the Analgesic Flupirtine Linked to Potassium KV7 Channel Opening Activity But Not Hepatocyte Toxicity

“…[1] The mechanism of action of flupirtine has been attributed to the ability of the drug to open voltage-gated K + channels (K V ) in the central nervous system, which indirectly leads to antagonism of N-methyl-d-aspartate (NMDA) receptors. [2] Depending on the primary factors that lead to channel opening and closing, ion channels are divided into ligand-or voltage-gated subfamilies, with or without a physiological ligand binding site. [3] Even in the latter case, modulation by small molecules is conceivable, and both subfamilies are druggable.…”

“…Flupirtine (1), retigabine(2), and their putative oxidation products (1 a,b and 2 a,b, respectively) in comparison with acetaminophen (3) and its known metabolite N-acetyl-p-quinone imine (NAPQI, 3 a).…”