Tezampanel

Tezampanel (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name) (developmental code names LY-293,558, LY-326,325, 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

Clinical data
Other names	LY-293,558; LY-293558; LY293558; LY-326,325; LY-326325; LY326325; NGX-424; NGX424
Routes of administration	IV
ATC code	none
Legal status
Legal status	Investigational
Identifiers
IUPAC name (3S,4aR,6R,8aR)-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid
CAS Number	154652-83-2 Y
PubChem CID	127894
IUPHAR/BPS	4245
ChemSpider	113428 N
UNII	GA36S2O9C2
KEGG	D06656 N
ChEMBL	ChEMBL14935 N
Chemical and physical data
Formula	C13H21N5O2
Molar mass	279.344 g·mol−1
3D model (JSmol)	Interactive image
SMILES C1C[C@H]2CN[C@@H](C[C@H]2C[C@H]1CCC3=NNN=N3)C(=O)O
InChI InChI=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 N Key:ZXFRFPSZAKNPQQ-YTWAJWBKSA-N N
NY (what is this?)  (verify)

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]

Whereas tezampanel free base is known as LY-293558, tezampanel hydrochloride is said to be known as LY-326325.^[20][21]

References

1. Gilron I (September 2001). "LY-293558. Eli Lilly & Co". Current Opinion in Investigational Drugs. 2 (9): 1273–8. PMID 11717815.
2. Ornstein PL, Arnold MB, Augenstein NK, Lodge D, Leander JD, Schoepp DD (July 1993). "(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. doi:10.1021/jm00066a016. PMID 8393116.
3. Schoepp DD, Lodge D, Bleakman D, Leander JD, Tizzano JP, Wright RA, et al. (September 1995). "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. doi:10.1016/0028-3908(95)00099-r. PMID 8532186. S2CID 26092003.
4. Bleakman R, Schoepp DD, Ballyk B, Bufton H, Sharpe EF, Thomas K, et al. (April 1996). "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. PMID 8609884.
5. Li H, Rogawski MA (1998). "GluR5 kainate receptor mediated synaptic transmission in rat basolateral amygdala in vitro". Neuropharmacology. 37 (10–11): 1279–86. doi:10.1016/s0028-3908(98)00109-9. PMID 9849665. S2CID 22283402.
6. Bullock R, Graham DI, Swanson S, McCulloch J (May 1994). "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. doi:10.1038/jcbfm.1994.57. PMID 8163588.
7. Rogawski MA, Kurzman PS, Yamaguchi SI, Li H (2001). "Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse". Neuropharmacology. 40 (1): 28–35. doi:10.1016/s0028-3908(00)00112-x. PMID 11077068. S2CID 1616466.
8. Liljequist S, Cebers G, Kalda A (November 1995). "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. doi:10.1016/0006-2952(95)02032-2. PMID 8615854.
9. Rasmussen K, Kendrick WT, Kogan JH, Aghajanian GK (November 1996). "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. doi:10.1016/S0893-133X(96)00094-2. PMID 8914123.
10. Kest B, McLemore G, Kao B, Inturrisi CE (December 1997). "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. PMID 9400000.
11. McLemore GL, Kest B, Inturrisi CE (December 1997). "The effects of LY293558, an AMPA receptor antagonist, on acute and chronic morphine dependence". Brain Research. 778 (1): 120–6. doi:10.1016/s0006-8993(97)00985-2. PMID 9462883. S2CID 30430984.
12. Carlezon WA, Rasmussen K, Nestler EJ (March 1999). "AMPA antagonist LY293558 blocks the development, without blocking the expression, of behavioral sensitization to morphine". Synapse. 31 (4): 256–62. doi:10.1002/(SICI)1098-2396(19990315)31:4<256::AID-SYN3>3.0.CO;2-E. PMID 10051106. S2CID 30152197.
13. Sang CN, Hostetter MP, Gracely RH, Chappell AS, Schoepp DD, Lee G, et al. (November 1998). "AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans". Anesthesiology. 89 (5): 1060–7. doi:10.1097/00000542-199811000-00005. PMID 9821993. S2CID 34676979.
14. Gilron I, Max MB, Lee G, Booher SL, Sang CN, Chappell AS, Dionne RA (September 2000). "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. doi:10.1067/mcp.2000.108677. PMID 11014414. S2CID 8816761.
15. Von Bergen NH, Subieta A, Brennan TJ (July 2002). "Effect of intrathecal non-NMDA EAA receptor antagonist LY293558 in rats: a new class of drugs for spinal anesthesia". Anesthesiology. 97 (1): 177–82. doi:10.1097/00000542-200207000-00025. PMID 12131120. S2CID 26550939.
16. Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, et al. (July 2004). "LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine". Cephalalgia. 24 (7): 596–602. doi:10.1111/j.1468-2982.2004.00723.x. PMID 15196302. S2CID 37366020.
17. Lee HJ, Pogatzki-Zahn EM, Brennan TJ (October 2006). "The effect of the AMPA/kainate receptor antagonist LY293558 in a rat model of postoperative pain". The Journal of Pain. 7 (10): 768–77. doi:10.1016/j.jpain.2006.03.010. PMID 17018337.
18. Jin HC, Keller AJ, Jung JK, Subieta A, Brennan TJ (October 2007). "Epidural tezampanel, an AMPA/kainate receptor antagonist, produces postoperative analgesia in rats". Anesthesia and Analgesia. 105 (4): 1152–9, table of contents. doi:10.1213/01.ane.0000281435.58012.e3. PMID 17898404. S2CID 16239521.
19. Alt A, Weiss B, Ogden AM, Li X, Gleason SD, Calligaro DO, et al. (April 2006). "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. doi:10.1007/s00213-005-0292-0. PMID 16470401. S2CID 12559816.
20. Larsen AM, Bunch L (February 2011). "Medicinal chemistry of competitive kainate receptor antagonists". ACS Chem Neurosci. 2 (2): 60–74. doi:10.1021/cn1001039. PMC 3369727. PMID 22778857.
21. Bleakman D, Gates MR, Ogden AM, Mackowiak M (2002). "Kainate receptor agonists, antagonists and allosteric modulators". Curr Pharm Des. 8 (10): 873–85. doi:10.2174/1381612024607108. PMID 11945137.