Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors.

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Rodriguez-Munoz M, Sanchez-Blazquez P, Garzon J

Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors.

Oncotarget. 2018 May 4;9(34):23373-23389. doi: 10.18632/oncotarget.25169. eCollection 2018 May 4.

PubMed ID

29805740 [ View in PubMed

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Abstract

Fenfluramine exhibits antiepileptic properties and thus diminishes epileptiform discharges in experimental animal models of Dravet syndrome. Fenfluramine is metabolized into norfenfluramine in vivo, which shows greater affinity and agonist activity at serotonin 5HT2 receptors (5HT2R) than fenfluramine. In this study, we found that fenfluramine and norfenfluramine disrupted the regulatory association of the sigma 1 receptor (sigma1R) with NR1 subunits of glutamate N-methyl-D-aspartate receptors (NMDAR), an effect that was also produced by sigma1R antagonists such as S1RA and prevented by sigma1R agonists such as PPCC. The antagonists removed sigma1R bound to NMDAR NR1 subunits enabling calcium-regulated calmodulin (CaM) to bind to those subunits. As a result, CaM may inhibit calcium permeation through NMDARs. The serotoninergic activity of fenfluramine at 5HT2AR, and likely also at 5HT2CR, collaborated with its activity at sigma1Rs to prevent the convulsive syndrome promoted by NMDAR overactivation. Notably, fenfluramine enhanced the inhibitory coupling of G protein-coupled receptors such as 5HT1AR and cannabinoid type 1 receptor with NMDARs, thus allowing the more effective restrain of NMDAR activity. Thus, fenfluramine circumvents the negative side effects of direct NMDAR antagonists and may improve the quality of life of subjects affected by such proconvulsant dysfunctions.

DrugBank Data that Cites this Article

Drugs

Fenfluramine

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Fenfluramine	5-hydroxytryptamine receptor 1A	Protein	Humans	No	Agonist	Details
Fenfluramine	5-hydroxytryptamine receptor 2A	Protein	Humans	Unknown	Agonist	Details
Fenfluramine	5-hydroxytryptamine receptor 2C	Protein	Humans	Yes	Agonist	Details
Fenfluramine	Sigma non-opioid intracellular receptor 1	Protein	Humans	Yes	Antagonist	Details