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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.[1]
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.[2] 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.[2][3] 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.[2][3]
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.[3] Recent advances in drug design, such as the development of neutral antagonists and multitarget ligands, may offer new opportunities for therapeutic intervention.[4][5]
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.[6] These studies included participants aged 55 to 90 years and employed multiple dosing regimens.[6]
↑Drop M, Koczurkiewicz-Adamczyk P, Bento O, Pietruś W, Satała G, Blicharz-Futera K, Canale V, Grychowska K, Bantreil X, Pękala E, Kurczab R, Bojarski AJ, Chaumont-Dubel S, Marin P, Lamaty F, Zajdel P (September 2024). "5-HT6 receptor neutral antagonists protect astrocytes: A lesson from 2-phenylpyrrole derivatives". European Journal of Medicinal Chemistry. 275. doi:10.1016/j.ejmech.2024.116615. PMID38936149Check |pmid= value (help). Unknown parameter |article-number= ignored (help)
↑van Loevezijn A, Venhorst J, Iwema Bakker WI, de Korte CG, de Looff W, Verhoog S, van Wees JW, van Hoeve M, van de Woestijne RP, van der Neut MA, Borst AJ, van Dongen MJ, de Bruin NM, Keizer HG, Kruse CG (October 2011). "N'-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT₆R) antagonists with unique structural features". Journal of Medicinal Chemistry. 54 (20): 7030–7054. doi:10.1021/jm200466r. PMID21866910.
