By generating novel clemalogues, we determined that compounds capable of suppressing spontaneous seizures in vivo had a binding preference to 5-HT2BR. Additionally, we present pharmacological data which suggest that activation of 5-HT2BR may be the common antiepileptic mechanism of action shared by the 5-HT modulating compounds showing efficacy in clinical trials and validated preclinical models of Dravet syndrome. Here, HTR5A is linked to encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy.