Chemistry:ABT-354

ABT-354 (also known as SLV-354 or SLV354) is an investigational small molecule drug developed by AbbVie, Inc. as a selective antagonist of the serotonin 5-HT₆ receptor (HTR6), with intended applications in the treatment of cognitive disorders such as mild-to-moderate Alzheimer’s disease.

Mechanism of action

ABT-354 selectively antagonizes the 5-HT₆ receptor, a G protein-coupled receptor almost exclusively expressed in the central nervous system (CNS), where it modulates neurotransmitter systems including acetylcholine, glutamate, dopamine, and norepinephrine. Blockade of 5-HT₆ receptors has been shown in preclinical models to enhance cholinergic and glutamatergic neurotransmission, leading to improvements in cognitive performance and memory. Evidence from animal studies indicates that both 5-HT₆ receptor antagonists and agonists can paradoxically exert procognitive, antidepressant, and anxiolytic effects, demonstrates the complex pharmacology of this receptor class.

Other 5-HT₆ antagonists

Despite promising preclinical results, several selective 5-HT₆ receptor antagonists (e.g., idalopirdine, intepirdine) have failed to demonstrate significant cognitive benefits in late-stage clinical trials for Alzheimer’s disease, possibly due to the complexity of the disorder and the need for multitarget approaches. Recent advances in drug design, such as the development of neutral antagonists and multitarget ligands, may offer new opportunities for therapeutic intervention.

Clinical trials

Clinical trials for ABT-354 have focused on assessing its safety, tolerability, and pharmacokinetics in patients with mild-to-moderate Alzheimer’s disease who are concurrently receiving stable doses of acetylcholinesterase inhibitors. These studies included participants aged 55 to 90 years and employed multiple dosing regimens.