Serotonin 5-HT2 receptors

Class

phenethylamine derivative; serotonin-releasing agent and 5-HT2 receptor agonist

Pathway

the precise mechanism by which fenfluramine exerts its anticonvulsant effect in Dravet syndrome and Lennox-Gastaut syndrome is unknown; fenfluramine and its active metabolite norfenfluramine exhibit agonist activity at serotonin 5-HT2 receptors

Serotonin 5-HT2 receptors are a family of G protein-coupled receptors (5-HT2A, 5-HT2B, and 5-HT2C subtypes) activated by the neurotransmitter serotonin throughout the central nervous system and peripheral tissues such as blood vessels and heart valves. Serotonin signaling broadly influences neuronal excitability, mood, appetite, and vascular tone, making these receptors a target for conditions ranging from psychiatric disorders to seizure syndromes. Fenfluramine is a phenethylamine compound that acts through a dual mechanism: it promotes release of serotonin from presynaptic nerve terminals, increasing the amount of serotonin available in the synapse, and its active metabolite, norfenfluramine, directly stimulates 5-HT2 receptors. This combined action raises serotonergic tone in the brain, which is thought to contribute to reduced seizure activity in certain severe, treatment-resistant childhood epilepsy syndromes, including Dravet syndrome and Lennox-Gastaut syndrome, although the precise anticonvulsant pathway remains incompletely defined. Because 5-HT2 receptors are expressed outside the brain as well, particularly in cardiac and pulmonary vascular tissue, modulating this system carries physiological considerations that extend beyond its central effects, illustrating the broader principle that receptors distributed across multiple organ systems produce both intended and unintended consequences when pharmacologically engaged.