Tezampanel

{{Short description|Chemical compound}}

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 398756829

| IUPAC_name = (3S,4aR,6R,8aR)-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid

| image = Tezampanel.svg

| width = 250

| tradename =

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| legal_US =

| legal_status = Investigational

| routes_of_administration = IV

| bioavailability =

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| IUPHAR_ligand = 4245

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 154652-83-2

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| ATC_prefix = none

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| PubChem = 127894

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

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| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = GA36S2O9C2

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 113428

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 14935

| KEGG_Ref = {{keggcite|changed|kegg}}

| KEGG = D06656

| synonyms = LY-293,558; LY-293558; LY293558; LY-326,325; LY-326325; LY326325; NGX-424; NGX424

| C=13 | H=21 | N=5 | O=2

| SMILES = C1C[C@H]2CN[C@@H](C[C@H]2C[C@H]1CCC3=NNN=N3)C(=O)O

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C13H21N5O2/c19-13(20)11-6-10-5-8(1-3-9(10)7-14-11)2-4-12-15-17-18-16-12/h8-11,14H,1-7H2,(H,19,20)(H,15,16,17,18)/t8-,9+,10-,11+/m1/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = ZXFRFPSZAKNPQQ-YTWAJWBKSA-N

}}

Tezampanel ({{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|USAN|United States Adopted Name}}) (developmental code names LY-293,558, LY-326,325, NGX-424) is a drug originally developed by Eli Lilly{{cite journal | vauthors = Gilron I | title = LY-293558. Eli Lilly & Co | journal = Current Opinion in Investigational Drugs | volume = 2 | issue = 9 | pages = 1273–8 | date = September 2001 | pmid = 11717815 }} which acts as a competitive antagonist of the AMPA and kainate subtypes of the ionotropic glutamate receptor family,{{cite journal | vauthors = Ornstein PL, Arnold MB, Augenstein NK, Lodge D, Leander JD, Schoepp DD | title = (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 = Journal of Medicinal Chemistry | volume = 36 | issue = 14 | pages = 2046–8 | date = July 1993 | pmid = 8393116 | doi = 10.1021/jm00066a016 }}{{cite journal | vauthors = Schoepp DD, Lodge D, Bleakman D, Leander JD, Tizzano JP, Wright RA, Palmer AJ, Salhoff CR, Ornstein PL | display-authors = 6 | title = 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 | journal = Neuropharmacology | volume = 34 | issue = 9 | pages = 1159–68 | date = September 1995 | pmid = 8532186 | doi = 10.1016/0028-3908(95)00099-r | s2cid = 26092003 }} with selectivity for the GluR5 subtype of the kainate receptor.{{cite journal | vauthors = Bleakman R, Schoepp DD, Ballyk B, Bufton H, Sharpe EF, Thomas K, Ornstein PL, Kamboj RK | display-authors = 6 | title = 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 | journal = Molecular Pharmacology | volume = 49 | issue = 4 | pages = 581–5 | date = April 1996 | pmid = 8609884 }}{{cite journal | vauthors = Li H, Rogawski MA | title = GluR5 kainate receptor mediated synaptic transmission in rat basolateral amygdala in vitro | journal = Neuropharmacology | volume = 37 | issue = 10–11 | pages = 1279–86 | pmid = 9849665 | doi = 10.1016/s0028-3908(98)00109-9 | year = 1998 | s2cid = 22283402 }} It has neuroprotective{{cite journal | vauthors = Bullock R, Graham DI, Swanson S, McCulloch J | title = Neuroprotective effect of the AMPA receptor antagonist LY-293558 in focal cerebral ischemia in the cat | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 14 | issue = 3 | pages = 466–71 | date = May 1994 | pmid = 8163588 | doi = 10.1038/jcbfm.1994.57 | doi-access = free }} and anticonvulsant properties,{{cite journal | vauthors = Rogawski MA, Kurzman PS, Yamaguchi SI, Li H | title = Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse | journal = Neuropharmacology | volume = 40 | issue = 1 | pages = 28–35 | pmid = 11077068 | doi = 10.1016/s0028-3908(00)00112-x | year = 2001 | s2cid = 1616466 }} the former of which may, at least in part, occur via blockade of calcium uptake into neurons.{{cite journal | vauthors = Liljequist S, Cebers G, Kalda A | title = 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 | journal = Biochemical Pharmacology | volume = 50 | issue = 11 | pages = 1761–74 | date = November 1995 | pmid = 8615854 | doi = 10.1016/0006-2952(95)02032-2 }}

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,{{cite journal | vauthors = Rasmussen K, Kendrick WT, Kogan JH, Aghajanian GK | title = A selective AMPA antagonist, LY293558, suppresses morphine withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal | journal = Neuropsychopharmacology | volume = 15 | issue = 5 | pages = 497–505 | date = November 1996 | pmid = 8914123 | doi = 10.1016/S0893-133X(96)00094-2 | doi-access = free }}{{cite journal | vauthors = Kest B, McLemore G, Kao B, Inturrisi CE | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 283 | issue = 3 | pages = 1249–55 | date = December 1997 | pmid = 9400000 }}{{cite journal | vauthors = McLemore GL, Kest B, Inturrisi CE | title = The effects of LY293558, an AMPA receptor antagonist, on acute and chronic morphine dependence | journal = Brain Research | volume = 778 | issue = 1 | pages = 120–6 | date = December 1997 | pmid = 9462883 | doi = 10.1016/s0006-8993(97)00985-2 | s2cid = 30430984 | doi-access = free }} and the development of tolerance,{{cite journal | vauthors = Carlezon WA, Rasmussen K, Nestler EJ | title = AMPA antagonist LY293558 blocks the development, without blocking the expression, of behavioral sensitization to morphine | journal = Synapse | volume = 31 | issue = 4 | pages = 256–62 | date = March 1999 | pmid = 10051106 | doi = 10.1002/(SICI)1098-2396(19990315)31:4<256::AID-SYN3>3.0.CO;2-E | s2cid = 30152197 | doi-access = free }} as well as having antihyperalgesic{{cite journal | vauthors = Sang CN, Hostetter MP, Gracely RH, Chappell AS, Schoepp DD, Lee G, Whitcup S, Caruso R, Max MB | display-authors = 6 | title = AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans | journal = Anesthesiology | volume = 89 | issue = 5 | pages = 1060–7 | date = November 1998 | pmid = 9821993 | doi = 10.1097/00000542-199811000-00005 | s2cid = 34676979 | doi-access = free }} and analgesic effects in its own right.{{cite journal | vauthors = Gilron I, Max MB, Lee G, Booher SL, Sang CN, Chappell AS, Dionne RA | title = Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain | journal = Clinical Pharmacology and Therapeutics | volume = 68 | issue = 3 | pages = 320–7 | date = September 2000 | pmid = 11014414 | doi = 10.1067/mcp.2000.108677 | s2cid = 8816761 }}{{cite journal | vauthors = Von Bergen NH, Subieta A, Brennan TJ | title = Effect of intrathecal non-NMDA EAA receptor antagonist LY293558 in rats: a new class of drugs for spinal anesthesia | journal = Anesthesiology | volume = 97 | issue = 1 | pages = 177–82 | date = July 2002 | pmid = 12131120 | doi = 10.1097/00000542-200207000-00025 | s2cid = 26550939 | doi-access = free }}{{cite journal | vauthors = 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 | display-authors = 6 | title = LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine | journal = Cephalalgia | volume = 24 | issue = 7 | pages = 596–602 | date = July 2004 | pmid = 15196302 | doi = 10.1111/j.1468-2982.2004.00723.x | s2cid = 37366020 }}{{cite journal | vauthors = Lee HJ, Pogatzki-Zahn EM, Brennan TJ | title = The effect of the AMPA/kainate receptor antagonist LY293558 in a rat model of postoperative pain | journal = The Journal of Pain | volume = 7 | issue = 10 | pages = 768–77 | date = October 2006 | pmid = 17018337 | doi = 10.1016/j.jpain.2006.03.010 | doi-access = free }}{{cite journal | vauthors = Jin HC, Keller AJ, Jung JK, Subieta A, Brennan TJ | title = Epidural tezampanel, an AMPA/kainate receptor antagonist, produces postoperative analgesia in rats | journal = Anesthesia and Analgesia | volume = 105 | issue = 4 | pages = 1152–9, table of contents | date = October 2007 | pmid = 17898404 | doi = 10.1213/01.ane.0000281435.58012.e3 | s2cid = 16239521 | doi-access = free }} It also has anxiolytic effects in animal studies and has been suggested as a candidate for the treatment of anxiety in humans.{{cite journal | vauthors = Alt A, Weiss B, Ogden AM, Li X, Gleason SD, Calligaro DO, Bleakman D, Witkin JM | display-authors = 6 | title = 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 | journal = Psychopharmacology | volume = 185 | issue = 2 | pages = 240–7 | date = April 2006 | pmid = 16470401 | doi = 10.1007/s00213-005-0292-0 | s2cid = 12559816 }}

Whereas tezampanel free base is known as LY-293558, tezampanel hydrochloride is said to be known as LY-326325.{{cite journal | vauthors = Larsen AM, Bunch L | title = Medicinal chemistry of competitive kainate receptor antagonists | journal = ACS Chem Neurosci | volume = 2 | issue = 2 | pages = 60–74 | date = February 2011 | pmid = 22778857 | pmc = 3369727 | doi = 10.1021/cn1001039 | url = }}{{cite journal | vauthors = Bleakman D, Gates MR, Ogden AM, Mackowiak M | title = Kainate receptor agonists, antagonists and allosteric modulators | journal = Curr Pharm Des | volume = 8 | issue = 10 | pages = 873–85 | date = 2002 | pmid = 11945137 | doi = 10.2174/1381612024607108 | url = }}