Centanafadine (Simtriyo®): a first-in-class triple reuptake inhibitor approved for attention-deficit/hyperactivity disorder (ADHD)

Abstract

Centanafadine (Simtriyo^®, 3) is a recently approved therapy for attention-deficit/hyperactivity disorder (ADHD) that introduces a first-in-class triple reuptake inhibition mechanism. Featuring a naphthyl group and a rigid azabicyclic scaffold, centanafadine functions as a norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) with a potency profile of NET > DAT > SERT. Unlike flexible phenethylamine stimulants such as (meth)amphetamine (1), which enter presynaptic neurons and actively trigger monoamine release, or piperidine derivatives like methylphenidate (2), which selectively block dopamine and norepinephrine reuptake, centanafadine inhibits all three monoamine transporters without inducing neurotransmitter release. Centanafadine represents a modern medicinal chemistry strategy aimed at managing ADHD symptoms through combined catecholaminergic and serotonergic mechanisms, offering sustained efficacy while potentially mitigating the abuse liability, insomnia, and cardiovascular risks typical of traditional psychostimulants.