Homotaurine Explained

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.

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.[2] A study in cognitive impairment done in 2018 did show positive benefits.[3]

Homotaurine is currently in a phase 3 study with expected FDA approval as the first disease modifying drug for AD.[4] [5]

Medical use

Acamprosate (N-acetyl homotaurine) was approved by the FDA in 2004 to treat alcohol dependence.[6]

Biochemical properties

In preclinical studies it had been found to bind to soluble amyloid beta and inhibit the formation of neurotoxic aggregates.[2] [7] Homotaurine has also shown anticonvulsant activities, reduction in skeletal muscle tonus, and hypothermic activity.

Homotaurine has been reported as a GABA antagonist,[6] 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.[4]

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]

Notes and References

  1. Martorana . Alessandro . Di Lorenzo . Francesco . Manenti . Guglielmo . Semprini . Roberta . Koch . Giacomo . Homotaurine Induces Measurable Changes of Short Latency Afferent Inhibition in a Group of Mild Cognitive Impairment Individuals . Frontiers in Aging Neuroscience . 23 September 2014 . 6 . 254 . 10.3389/fnagi.2014.00254 . 25295005 . 4172065 . free .
  2. Caltagirone . C . Ferrannini . L . Marchionni . N . Nappi . G . Scapagnini . G . Trabucchi . M . The potential protective effect of tramiprosate (homotaurine) against Alzheimer's disease: a review . Aging Clinical and Experimental Research . December 2012 . 24 . 6 . 580–587 . 10.3275/8585 . 22961121 . 10816430 .
  3. 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. . Effect of homotaurine in patients with cognitive impairment: results from an Italian observational retrospective study . Journal of Gerontology and Geriatrics . 15 March 2018 . 66 . 15–20 .
  4. Tolar . Martin . Abushakra . Susan . Hey . John A. . Porsteinsson . Anton . Sabbagh . Marwan . Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer's disease with potential for near term approval . Alzheimer's Research & Therapy . December 2020 . 12 . 1 . 95 . 10.1186/s13195-020-00663-w . 32787971 . 7424995 . free .
  5. Abushakra . S. . Porsteinsson . A. . Scheltens . P. . Sadowsky . C. . Vellas . B. . Cummings . J. . Gauthier . S. . Hey . J. A. . Power . A. . Wang . P. . Tolar . M. . Tolar . M . Clinical effects of tramiprosate in apoe4/4 homozygous patients with mild alzheimer's disease suggest disease modification potential . Journal of Prevention of Alzheimer's Disease . 1 September 2017 . 4 . 3 . 149–156 . 10.14283/jpad.2017.26 . 29182706 . 44515548 . free .
  6. Book: Lednicer . Daniel . vanc . The Organic Chemistry of Drug Synthesis . 2008 . John Wiley & Sons . Hoboken . 978-0-470-18066-2 . 7th . 15 .
  7. Aisen . Paul . Gauthier . Serge . Vellas . Bruno . Briand . Richard . Saumier . Daniel . Laurin . Julie . Garceau . Denis . Alzhemed: A Potential Treatment for Alzheimers Disease . Current Alzheimer Research . 1 September 2007 . 4 . 4 . 473–478 . 10.2174/156720507781788882 . 17908052 .
  8. Book: Lajtha . Abel . Metabolism in the Nervous System . 2013 . Springer Science & Business Media . 978-1-4684-4367-7 . 520 .
  9. Book: Tashjian . Armen H. . Armstrong . Ehrin J. . Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy . 2011 . Lippincott Williams & Wilkins . 978-1-4511-1805-6 . 308 .
  10. Reyes-Haro . Daniel . Cabrera-Ruíz . Elizabeth . Estrada-Mondragón . Argel . Miledi . Ricardo . Martínez-Torres . Ataúlfo . Modulation of GABA-A receptors of astrocytes and STC-1 cells by taurine structural analogs . Amino Acids . November 2014 . 46 . 11 . 2587–2593 . 10.1007/s00726-014-1813-0 . 25119985 . 10319072 .
  11. Giotti . A. . Luzzi . S. . Spagnesi . S. . Zilletti . L. . Homotaurine: a GABAB antagonist in guinea-pig ileum. . British Journal of Pharmacology . August 1983 . 79 . 4 . 855–862 . 10.1111/j.1476-5381.1983.tb10529.x . 6652358 . 2044932 .
  12. Mehta . A . Ticku . M . Baclofen induces catatonia in rats . Neuropharmacology . September 1987 . 26 . 9 . 1419–1423 . 10.1016/0028-3908(87)90108-0 . 2823166 . 24010833 .
  13. Serrano . M.Isabel . Serrano . Jose S. . Fernández . Ana . Asadi . Ihklas . Serrano-Martino . M.Carmen . GABAB Receptors and Opioid Mechanisms Involved in Homotaurine-Induced Analgesia . General Pharmacology: The Vascular System . March 1998 . 30 . 3 . 411–415 . 10.1016/s0306-3623(97)00279-6 . 9510095 .
  14. Serrano . Maria Isabel . Serrano . Jose S. . Asadi . Ikhlas . Fernandez . Ana . Serrano-Martino . Maria Carmen . Role of K+-channels in homotaurine-induced analgesia . Fundamental and Clinical Pharmacology . 16 June 2001 . 15 . 3 . 167–173 . 10.1046/j.1472-8206.2001.00026.x . 11468027 . 19694376 .
  15. Olive . M.Foster . Nannini . Michelle A . Ou . Christine J . Koenig . Heather N . Hodge . Clyde W . Effects of acute acamprosate and homotaurine on ethanol intake and ethanol-stimulated mesolimbic dopamine release . European Journal of Pharmacology . February 2002 . 437 . 1–2 . 55–61 . 10.1016/s0014-2999(02)01272-4 . 11864639 .

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