Tezampanel Explained

Tezampanel (INN, USAN) (code names LY-293,558, NGX-424) is a drug originally developed by Eli Lilly[1] which acts as a competitive antagonist of the AMPA and kainate subtypes of the ionotropic glutamate receptor family,[2] [3] with selectivity for the GluR5 subtype of the kainate receptor.[4] [5] It has neuroprotective[6] and anticonvulsant properties,[7] the former of which may, at least in part, occur via blockade of calcium uptake into neurons.[8]

Tezampanel has a range of effects which may be useful for medicinal purposes, as well as its applications in scientific research. It suppresses both the withdrawal symptoms from morphine and other opioids,[9] [10] [11] and the development of tolerance,[12] as well as having antihyperalgesic[13] and analgesic effects in its own right.[14] [15] [16] [17] [18] It also has anxiolytic effects in animal studies and has been suggested as a candidate for the treatment of anxiety in humans.[19]

Notes and References

  1. Gilron I . LY-293558. Eli Lilly & Co . Current Opinion in Investigational Drugs . 2 . 9 . 1273–8 . September 2001 . 11717815 .
  2. Ornstein PL, Arnold MB, Augenstein NK, Lodge D, Leander JD, Schoepp DD . (3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3 - carboxylic acid: a structurally novel, systemically active, competitive AMPA receptor antagonist . Journal of Medicinal Chemistry . 36 . 14 . 2046–8 . July 1993 . 8393116 . 10.1021/jm00066a016 .
  3. Schoepp DD, Lodge D, Bleakman D, Leander JD, Tizzano JP, Wright RA, Palmer AJ, Salhoff CR, Ornstein PL . 6 . In vitro and in vivo antagonism of AMPA receptor activation by (3S, 4aR, 6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl) ethyl] decahydroisoquinoline-3-carboxylic acid . Neuropharmacology . 34 . 9 . 1159–68 . September 1995 . 8532186 . 10.1016/0028-3908(95)00099-r . 26092003 .
  4. Bleakman R, Schoepp DD, Ballyk B, Bufton H, Sharpe EF, Thomas K, Ornstein PL, Kamboj RK . 6 . Pharmacological discrimination of GluR5 and GluR6 kainate receptor subtypes by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahyd roisdoquinoline-3 carboxylic-acid . Molecular Pharmacology . 49 . 4 . 581–5 . April 1996 . 8609884 .
  5. Li H, Rogawski MA . GluR5 kainate receptor mediated synaptic transmission in rat basolateral amygdala in vitro . Neuropharmacology . 37 . 10–11 . 1279–86 . 9849665 . 10.1016/s0028-3908(98)00109-9 . 1998 . 22283402 .
  6. Bullock R, Graham DI, Swanson S, McCulloch J . Neuroprotective effect of the AMPA receptor antagonist LY-293558 in focal cerebral ischemia in the cat . Journal of Cerebral Blood Flow and Metabolism . 14 . 3 . 466–71 . May 1994 . 8163588 . 10.1038/jcbfm.1994.57 . free .
  7. Rogawski MA, Kurzman PS, Yamaguchi SI, Li H . Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse . Neuropharmacology . 40 . 1 . 28–35 . 11077068 . 10.1016/s0028-3908(00)00112-x . 2001 . 1616466 .
  8. Liljequist S, Cebers G, Kalda A . Effects of decahydroisoquinoline-3-carboxylic acid monohydrate, a novel AMPA receptor antagonist, on glutamate-induced CA2+ responses and neurotoxicity in rat cortical and cerebellar granule neurons . Biochemical Pharmacology . 50 . 11 . 1761–74 . November 1995 . 8615854 . 10.1016/0006-2952(95)02032-2 .
  9. Rasmussen K, Kendrick WT, Kogan JH, Aghajanian GK . A selective AMPA antagonist, LY293558, suppresses morphine withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal . Neuropsychopharmacology . 15 . 5 . 497–505 . November 1996 . 8914123 . 10.1016/S0893-133X(96)00094-2 . free .
  10. Kest B, McLemore G, Kao B, Inturrisi CE . The competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist LY293558 attenuates and reverses analgesic tolerance to morphine but not to delta or kappa opioids . The Journal of Pharmacology and Experimental Therapeutics . 283 . 3 . 1249–55 . December 1997 . 9400000 .
  11. McLemore GL, Kest B, Inturrisi CE . The effects of LY293558, an AMPA receptor antagonist, on acute and chronic morphine dependence . Brain Research . 778 . 1 . 120–6 . December 1997 . 9462883 . 10.1016/s0006-8993(97)00985-2 . 30430984 . free .
  12. Carlezon WA, Rasmussen K, Nestler EJ . AMPA antagonist LY293558 blocks the development, without blocking the expression, of behavioral sensitization to morphine . Synapse . 31 . 4 . 256–62 . March 1999 . 10051106 . 10.1002/(SICI)1098-2396(19990315)31:4<256::AID-SYN3>3.0.CO;2-E . 30152197 . free .
  13. Sang CN, Hostetter MP, Gracely RH, Chappell AS, Schoepp DD, Lee G, Whitcup S, Caruso R, Max MB . 6 . AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans . Anesthesiology . 89 . 5 . 1060–7 . November 1998 . 9821993 . 10.1097/00000542-199811000-00005 . 34676979 . free .
  14. Gilron I, Max MB, Lee G, Booher SL, Sang CN, Chappell AS, Dionne RA . Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain . Clinical Pharmacology and Therapeutics . 68 . 3 . 320–7 . September 2000 . 11014414 . 10.1067/mcp.2000.108677 . 8816761 .
  15. Von Bergen NH, Subieta A, Brennan TJ . Effect of intrathecal non-NMDA EAA receptor antagonist LY293558 in rats: a new class of drugs for spinal anesthesia . Anesthesiology . 97 . 1 . 177–82 . July 2002 . 12131120 . 10.1097/00000542-200207000-00025 . 26550939 . free .
  16. Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LA, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F . 6 . LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine . Cephalalgia . 24 . 7 . 596–602 . July 2004 . 15196302 . 10.1111/j.1468-2982.2004.00723.x . 37366020 .
  17. Lee HJ, Pogatzki-Zahn EM, Brennan TJ . The effect of the AMPA/kainate receptor antagonist LY293558 in a rat model of postoperative pain . The Journal of Pain . 7 . 10 . 768–77 . October 2006 . 17018337 . 10.1016/j.jpain.2006.03.010 . free .
  18. Jin HC, Keller AJ, Jung JK, Subieta A, Brennan TJ . Epidural tezampanel, an AMPA/kainate receptor antagonist, produces postoperative analgesia in rats . Anesthesia and Analgesia . 105 . 4 . 1152–9, table of contents . October 2007 . 17898404 . 10.1213/01.ane.0000281435.58012.e3 . 16239521 . free .
  19. Alt A, Weiss B, Ogden AM, Li X, Gleason SD, Calligaro DO, Bleakman D, Witkin JM . 6 . In vitro and in vivo studies in rats with LY293558 suggest AMPA/kainate receptor blockade as a novel potential mechanism for the therapeutic treatment of anxiety disorders . Psychopharmacology . 185 . 2 . 240–7 . April 2006 . 16470401 . 10.1007/s00213-005-0292-0 . 12559816 .

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