Homotaurine
Homotaurine, also known as tramiprosate (INN), 3-amino-1-propanesulfonic acid, or 3-APS, is a natural sulfonic acid found in seaweed.[1] It is analogous to taurine, but with an extra carbon in its chain. It has GABAergic activity, apparently by mimicking GABA, which it resembles.[2]
Homotaurine was investigated in a Phase III clinical trial as a potential treatment for Alzheimer's disease (AD) that did not show efficacy. However, post-hoc analyses have shown positive and significant effects of homotaurine on secondary endpoints and subgroups of patients, including a reduction in hippocampal volume loss and lower decline in memory function in the overall cohort, as well as a reduction in global cognitive decline in APOE4 allele carriers, suggesting a disease-modifying effect.[3] A study in cognitive impairment done in 2018 did show positive benefits.[4]
Homotaurine is currently in a phase 3 study with expected FDA approval as the first disease modifying drug for AD.[5][6]
Medical use
Acamprosate (N-acetyl homotaurine) was approved by the FDA in 2004 to treat alcohol dependence.[2]
Biochemical properties
In preclinical studies it had been found to bind to soluble amyloid beta and inhibit the formation of neurotoxic aggregates.[3][7] Homotaurine has also shown anticonvulsant activities, reduction in skeletal muscle tonus, and hypothermic activity.[8]
Homotaurine has been reported as a GABA antagonist,[2] as well as a GABA agonist.[8][9] In vitro studies have found that homotaurine is a GABAA partial agonist[10] as well as a GABAB receptor partial agonist with low efficacy, becoming an antagonist and displacing the full agonists GABA and baclofen at this receptor.[11] In a study in rats, homotaurine reversed the catatonia induced by baclofen (the prototypical GABAB agonist),[12] and was able to produce analgesia via the GABAB receptor, an effect that was abolished when CGP-35348, a GABAB receptor antagonist was applied.[13][14]
In a human study homotaurine selectively and fully inhibits the formation of Aβ42 oligomers at the clinical dose, without evidence of vasogenic edema.[5]
One study in rats showed that homotaurine suppressed ethanol-stimulated dopamine release, as well as ethanol intake and preference in rats in a way similar to the N-acetyl derivative of homotaurine, acamprosate.[15]
References
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