Homotaurine (also known astramiprosate (INN),3-amino-1-propanesulfonic acid, or3-APS) is a natural sulfonic acid found in seaweed.[3] It is analogous totaurine, but with an extra carbon in its chain. It hasGABAergic activity, apparently by mimicking GABA, which it resembles.[4]
Homotaurine was investigated in aPhase III clinical trial as a potential treatment forAlzheimer'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 adisease-modifying effect.[5] A study in cognitive impairment done in 2018 did show positive benefits.[6]
Homotaurine is currently in a phase 3 study with expected FDA approval as the first disease modifying drug for AD.[7][8]
In preclinical studies it had been found to bind to solubleamyloid beta and inhibit the formation of neurotoxic aggregates.[5][9] Homotaurine has also shownanticonvulsant activities, reduction in skeletalmuscle tonus, andhypothermic activity.[10]
Homotaurine has been reported as aGABA antagonist,[4] as well as a GABA agonist.[10][11]In vitro studies have found that homotaurine is aGABAA partial agonist[12] as well as aGABAB receptor partial agonist with low efficacy, becoming an antagonist and displacing the full agonists GABA andbaclofen at this receptor.[13] In a study in rats, homotaurine reversed thecatatonia induced bybaclofen (the prototypical GABAB agonist),[14] and was able to produce analgesia via the GABAB receptor, an effect that was abolished whenCGP-35348, a GABAB receptor antagonist was applied.[15][16]
In a human study homotaurine selectively and fully inhibits the formation of Aβ42 oligomers at the clinical dose, without evidence of vasogenic edema.[7]
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 theN-acetylderivative of homotaurine,acamprosate.[17]
^abCaltagirone, C; Ferrannini, L; Marchionni, N; Nappi, G; Scapagnini, G; Trabucchi, M (December 2012). "The potential protective effect of tramiprosate (homotaurine) against Alzheimer's disease: a review".Aging Clinical and Experimental Research.24 (6):580–587.doi:10.3275/8585.PMID22961121.S2CID10816430.
^Martorana, A.; Motta, C; Koch, G.; Massaia, M.; Mondino, S.; Raniero, I.; Vacca, A.; Di Lorenzo, F.; Cavallo, G.; Oddenino, E.; Pavanelli, E.; Maniscalco, M.; Montano, V.; Mastropietro, A.; Bellia, N. C.; Ciravegna, E.; La Rocca, M.; Vitale, E.; Lorico, F.; Zacchettin, B.; Scalise, A.; Codemo, A.; Gabelli, C.; Spano, M.; Poli, S.; Panuccio, D.; Bruno, P.; Alfieri, P.; Ruggiero, R.; Cursi, F.; Levi Della Vida, G. (15 March 2018)."Effect of homotaurine in patients with cognitive impairment: results from an Italian observational retrospective study".Journal of Gerontology and Geriatrics.66:15–20.
^Serrano, M.Isabel; Serrano, Jose S.; Fernández, Ana; Asadi, Ihklas; Serrano-Martino, M.Carmen (March 1998). "GABAB Receptors and Opioid Mechanisms Involved in Homotaurine-Induced Analgesia".General Pharmacology: The Vascular System.30 (3):411–415.doi:10.1016/s0306-3623(97)00279-6.PMID9510095.
^Serrano, Maria Isabel; Serrano, Jose S.; Asadi, Ikhlas; Fernandez, Ana; Serrano-Martino, Maria Carmen (16 June 2001). "Role of K+-channels in homotaurine-induced analgesia".Fundamental and Clinical Pharmacology.15 (3):167–173.doi:10.1046/j.1472-8206.2001.00026.x.PMID11468027.S2CID19694376.
^Olive, M.Foster; Nannini, Michelle A; Ou, Christine J; Koenig, Heather N; Hodge, Clyde W (February 2002). "Effects of acute acamprosate and homotaurine on ethanol intake and ethanol-stimulated mesolimbic dopamine release".European Journal of Pharmacology.437 (1–2):55–61.doi:10.1016/s0014-2999(02)01272-4.PMID11864639.
