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Gavestinel

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Title: Gavestinel  
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Subject: NMDA receptor antagonists, Glycine, A.C.E. mixture, MMPIP, LY-344,545
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Gavestinel

Gavestinel
Systematic (IUPAC) name
3-[(E)-3-anilino-3-oxoprop-1-enyl]-4,6-dichloro-1H-indole-2-carboxylic acid
Clinical data
Legal status
?
Identifiers
CAS number  YesY
ATC code None
PubChem
ChemSpider  N
UNII  N
ChEMBL  N
Synonyms GV-150,526A
Chemical data
Formula C18H12Cl2N2O3 
Mol. mass 375.205 g/mol
 N   

Gavestinel (GV-150,526) is a drug which acts as an NMDA antagonist, binding selectively to the glycine site on the NMDA receptor complex, rather than the glutamate site many NMDA antagonists bind to.[1] It is neuroprotective in animal studies and has been researched for the treatment of stroke, progressing as far as Phase II clinical trials in humans before being dropped for lack of efficacy.[2][3][4][5] Gavestinel lacks phencyclidine-like behavioural effects in animals and is considered unlikely to possess any abuse potential in humans.[6]

Clinical Studies

Gavestinel showed positive effects in preventing ischemic damage in preclinical trials in rodent stroke models. [7] In a later rendomized, placebo- controlled phase II study, gavestinel showed no adverse psychotomimetic or hemodynamic effects in acute stroke patients, which were very common in NMDA antagonists, compared to placebo group. [8] Later, in two large phase III randomized placebo- controlled clinical trials, a total of more than 3000 acute ischemic stroke patients were recruited for the outcome study of gavestinel. Patients were given an intravenous loading dose of 800 mg and 5 maintenance dose of 200 mg every 12 hours for three months. However, no significant improvement was seen compared to the placebo group. An improvement was only showed among young patients with mild stroke in one of the two trials (GAIN Americas). But this was not found in another trial (GAIN International). [9][10]A MRI substudy was consistent with these trials. Treatment of gavestinel had no significant effects on ischemic infarction and attenuating cortical lesion growth. [11]

References

  1. ^ Chopra B, Chazot PL, Stephenson FA. Characterization of the binding of two novel glycine site antagonists to cloned NMDA receptors: evidence for two pharmacological classes of antagonists. British Journal of Pharmacology. 2000 May;130(1):65-72. PMID 10780999
  2. ^ Di Fabio R, Capelli AM, Conti N, Cugola A, Donati D, Feriani A, Gastaldi P, Gaviraghi G, Hewkin CT, Micheli F, Missio A, Mugnaini M, Pecunioso A, Quaglia AM, Ratti E, Rossi L, Tedesco G, Trist DG, Reggiani A (March 1997). "Substituted indole-2-carboxylates as in vivo potent antagonists acting as the strychnine-insensitive glycine binding site". Journal of Medicinal Chemistry 40 (6): 841–50.  
  3. ^ Bordi F, Pietra C, Ziviani L, Reggiani A (June 1997). "The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAo model of focal ischemia in the rat". Experimental Neurology 145 (2 Pt 1): 425–33.  
  4. ^ Lees KR, Lavelle JF, Cunha L, Diener HC, Sanders EA, Tack P, Wester P. Glycine antagonist (GV150526) in acute stroke: a multicentre, double-blind placebo-controlled phase II trial. Cerebrovascular Diseases. 2001;11(1):20-9. PMID 11173790
  5. ^ Haley EC, Thompson JL, Levin B, Davis S, Lees KR, Pittman JG, DeRosa JT, Ordronneau P, Brown DL, Sacco RL (May 2005). "Gavestinel does not improve outcome after acute intracerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies". Stroke; a Journal of Cerebral Circulation 36 (5): 1006–10.  
  6. ^ Beardsley PM, Ratti E, Balster RL, Willetts J, Trist D (November 2002). "The selective glycine antagonist gavestinel lacks phencyclidine-like behavioral effects". Behavioural Pharmacology 13 (7): 583–92.  
  7. ^ Bordi, F., Pietra, C., Ziviani, L., & Reggiani, A. (1997). The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAo model of focal ischemia in the rat. Experimental neurology, 145(2), 425-433.
  8. ^ Dyker, A. G., & Lees, K. R. (1999). Safety and tolerability of GV150526 (a glycine site antagonist at the N-methyl-D-aspartate receptor) in patients with acute stroke. Stroke, 30(5), 986-992.
  9. ^ Lees, K. R., Asplund, K., Carolei, A., Davis, S. M., Diener, H. C., Kaste, M., ... & Whitehead, J. (2000). Glycine Antagonist (gavestinel) in Neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. The Lancet, 355(9219), 1949-1954.
  10. ^ Sacco, R. L., DeRosa, J. T., Haley Jr, E. C., Levin, B., Ordronneau, P., Phillips, S. J., ... & GAIN Americas Investigators. (2001). Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. Jama, 285(13), 1719-1728.
  11. ^ Warach, S., Kaufman, D., Chiu, D., Devlin, T., Luby, M., Rashid, A., ... & Fisher, M. (2006). Effect of the glycine antagonist gavestinel on cerebral infarcts in acute stroke patients, a randomized placebo-controlled trial: the GAIN MRI Substudy. Cerebrovascular Diseases, 21(1-2), 106-111.


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