Serotonin receptors (5-HT)

Class

small molecule; first-generation H1 antihistamine (used clinically 1959-1976) repurposed for Dravet syndrome via a zebrafish phenotypic drug screen

Pathway

Per Epygenix's FDA IND press release, EPX-100's antiepileptic effect 'is not through a histaminergic mechanism of action, but via modulation of serotonin (5HT) signaling pathways'; the precise receptor subtype and downstream mechanism are not established.

Serotonin (5-hydroxytryptamine, or 5-HT) receptors are a large family of cell-surface proteins that respond to the neurotransmitter serotonin. With one exception they are G-protein-coupled receptors distributed throughout the central nervous system and periphery, where they regulate mood, sleep, gut motility, vascular tone, and neuronal excitability. Because serotonergic signaling can either dampen or heighten neuronal firing depending on which receptor subtype and brain region is engaged, this system is a longstanding target in psychiatry, gastroenterology, and increasingly in epilepsy. In seizure disorders, certain 5-HT receptor subtypes on inhibitory and excitatory neurons help set the threshold at which abnormal, synchronized electrical activity propagates; enhancing or dampening specific subtypes can raise that threshold and reduce seizure frequency. This mechanism is of particular interest in rare, severe childhood epilepsies such as Dravet syndrome, where existing antiseizure medicines are often only partially effective. Notably, some compounds originally developed for unrelated indications, such as older antihistamines, have been found through phenotypic screening to have antiseizure activity that appears to run through serotonergic rather than histaminergic pathways, illustrating how a drug's clinically relevant target can differ from the one it was originally designed against.