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α-Methyltryptophan

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α-Methyltryptophan
Clinical data
Other namesαMTP; α-MTP; AMTP; α-Methyl-L-tryptophan; alpha-Methyltryptophan; alpha-Methyl-L-tryptophan
Drug classSerotonin receptor agonist
Identifiers
  • (2S)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoic acid
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC12H14N2O2
Molar mass218.256 g·mol−1
3D model (JSmol)
  • C[C@](CC1=CNC2=CC=CC=C21)(C(=O)O)N
  • InChI=1S/C12H14N2O2/c1-12(13,11(15)16)6-8-7-14-10-5-3-2-4-9(8)10/h2-5,7,14H,6,13H2,1H3,(H,15,16)/t12-/m0/s1
  • Key:ZTTWHZHBPDYSQB-LBPRGKRZSA-N

α-Methyltryptophan (αMTP or α-MTP) is a synthetic tryptamine derivative, an artificial amino acid, and a prodrug of α-methylserotonin (αMS).[1][2][3] It is the α-methylated derivative of tryptophan, while αMS is the α-methylated analogue of serotonin.[1][3] αMTP has been suggested for potential therapeutic use in the treatment of conditions thought by some authors to be related to serotonin deficiency, such as depression.[1] In labeled forms, αMTP is also used as a radiotracer in positron emission tomography (PET) imaging to assess serotonin synthesis and certain other processes.[4][2][5][6][7]

αMS is a non-selective serotonin receptor agonist, including of the serotonin 5-HT2 receptors, and has been described as a "substitute neurotransmitter" of serotonin.[1][8][9][10] However, whereas αMS itself is too hydrophilic to efficiently cross the blood–brain barrier, thus being peripherally selective, αMTP is able to cross the blood–brain barrier and, following transformation, deliver αMS into the brain.[1][4]

Besides αMS, αMTP is also metabolized into α-methyltryptamine (αMT).[11][12] αMT is a serotonin–norepinephrine–dopamine releasing agent, a non-selective serotonin receptor agonist, and a serotonergic psychedelic.[13][14] However, αMT levels are much lower than those of αMS with αMTP and αMT is described as a minor metabolite of αMTP.[11][12] In accordance, the behavioral effects of αMTP and αMT in animals are described as strikingly different.[12] α-Methylmelatonin can also be formed in small amounts from αMTP, but the formation of this compound with αMTP in vivo appears to be negligible.[15]

αMTP and αMS remain in the body for long amounts of time following a single dose of αMTP, whereas tryptophan results in only a short-lasting increase in brain serotonin levels.[1][5] This is attributed to the resistance to metabolism of these compounds afforded by their α-methyl group.[1] As such, αMTP might be advantageous for therapeutic purposes relative to tryptophan.[1] αMTP is useful over tryptophan in PET imaging because αMTP, unlike tryptophan, is not incorporated as an amino acid into brain proteins, and because, unlike serotonin, αMS is not a substrate for monoamine oxidase (MAO) and hence remains in the brain for a much longer amount of time.[3][4][5] The preceding limitations of tryptophan make its use in PET imaging in humans impossible, whereas αMTP is a viable agent for such purposes.[5]

αMTP is first converted by tryptophan hydroxylase into α-methyl-5-hydroxytryptophan (αM-5-HTP or α-methyl-5-HTP), the α-methylated analogue of 5-hydroxytryptophan (5-HTP), prior to being decarboxylated by aromatic L-amino acid decarboxylase (AAAD) into αMS.[1][4][3][5] αM-5-HTP has also been suggested for potential therapeutic use.[1] However, αM-5-HTP is also a tyrosine hydroxylase inhibitor similarly to α-methyltyrosine, as well as an AAAD inhibitor, and has been found to deplete levels of brain norepinephrine in animals, although not levels of brain dopamine.[1][16][17][18]

See also

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References

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  1. ^ a b c d e f g h i j k Sourkes TL (1991). "Alpha-methyltryptophan as a therapeutic agent". Prog Neuropsychopharmacol Biol Psychiatry. 15 (6): 935–938. doi:10.1016/0278-5846(91)90020-2. PMID 1763198.
  2. ^ a b Sourkes TL (1993). "Conversion of alpha-methyltryptophan to alpha-methylserotonin in vivo. New techniques for imaging serotonin". Adv Neurol. 60: 515–518. PMID 8420181.
  3. ^ a b c d Diksic M (September 2001). "Labelled alpha-methyl-L-tryptophan as a tracer for the study of the brain serotonergic system". J Psychiatry Neurosci. 26 (4): 293–303. PMC 167183. PMID 11590969.
  4. ^ a b c d Diksic M, Young SN (September 2001). "Study of the brain serotonergic system with labeled alpha-methyl-L-tryptophan". J Neurochem. 78 (6): 1185–1200. doi:10.1046/j.1471-4159.2001.00536.x. PMID 11579128.
  5. ^ a b c d e Diksic M, Grdisa M (November 1995). "Alpha-methyl-L-tryptophan as a tracer to study brain serotonergic system". Neurochem Res. 20 (11): 1353–1360. doi:10.1007/BF00992511. PMID 8786822.
  6. ^ Chugani DC (October 2011). "α-methyl-L-tryptophan: mechanisms for tracer localization of epileptogenic brain regions". Biomark Med. 5 (5): 567–575. doi:10.2217/bmm.11.73. PMC 3399668. PMID 22003905.
  7. ^ Kumar A, Asano E, Chugani HT (October 2011). "α-[¹¹C]-methyl-L-tryptophan PET for tracer localization of epileptogenic brain regions: clinical studies". Biomark Med. 5 (5): 577–584. doi:10.2217/bmm.11.68. PMC 3226729. PMID 22003906.
  8. ^ Maroteaux L, Ayme-Dietrich E, Aubertin-Kirch G, Banas S, Quentin E, Lawson R, Monassier L (February 2017). "New therapeutic opportunities for 5-HT2 receptor ligands" (PDF). Pharmacol Ther. 170: 14–36. doi:10.1016/j.pharmthera.2016.10.008. PMID 27771435. alpha-methyl-5-HT is a non-selective nearly full agonist at 5-HT2 receptors with similar affinity to 5-HT2A 5-HT2B and 5-HT2C receptors (Jerman, et al., 2001; Knight, et al., 2004; Porter, et al., 1999).
  9. ^ Vickers SP, Easton N, Malcolm CS, Allen NH, Porter RH, Bickerdike MJ, Kennett GA (2001). "Modulation of 5-HT(2A) receptor-mediated head-twitch behaviour in the rat by 5-HT(2C) receptor agonists". Pharmacol Biochem Behav. 69 (3–4): 643–652. doi:10.1016/s0091-3057(01)00552-4. PMID 11509227.
  10. ^ Ismaiel AM, Titeler M, Miller KJ, Smith TS, Glennon RA (February 1990). "5-HT1 and 5-HT2 binding profiles of the serotonergic agents alpha-methylserotonin and 2-methylserotonin". Journal of Medicinal Chemistry. 33 (2): 755–758. doi:10.1021/jm00164a046. PMID 2299641.
  11. ^ a b Roberge AG, Missala K, Sourkes TL (March 1972). "Alpha-methyltryptophan: effects on synthesis and degradation of serotonin in the brain". Neuropharmacology. 11 (2): 197–209. doi:10.1016/0028-3908(72)90092-5. PMID 4260268.
  12. ^ a b c Marsden CA, Curzon G (1977). "Effects of p-chlorophenylalanine and alpha-methyltryptophan on behaviour and brain 5-hydroxyindoles". Neuropharmacology. 16 (7–8): 489–494. doi:10.1016/0028-3908(77)90006-5. PMID 144245.
  13. ^ Barceloux DG (20 March 2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. John Wiley & Sons. pp. 196–199. ISBN 978-0-471-72760-6.
  14. ^ Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB (October 2014). "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology (Berl). 231 (21): 4135–4144. doi:10.1007/s00213-014-3557-7. PMC 4194234. PMID 24800892.
  15. ^ Montine TJ, Missala K, Sourkes TL (January 1992). "Alpha-methyltryptophan metabolism in rat pineal gland and brain". J Pineal Res. 12 (1): 43–48. doi:10.1111/j.1600-079x.1992.tb00024.x. PMID 1564632.
  16. ^ Murphy GF, Sourkes TL (May 1961). "The action of antidecarboxylases on the conversion of 3,4-dihydroxyphenylalanine to dopamine in vivo". Arch Biochem Biophys. 93 (2): 338–343. doi:10.1016/0003-9861(61)90276-4. PMID 13726974.
  17. ^ Tabei R, Spector S, Louis WJ, Sjoerdsma A (July 1969). "Antihypertensive and noradrenaline-depleting effects of alpha-methyl-5-hydroxytryptophan in the rat". Eur J Pharmacol. 7 (1): 39–44. doi:10.1016/0014-2999(69)90160-5. PMID 5307150.
  18. ^ Dominic JA, Moore KE (December 1969). "Behavioral and catecholamine depleting effects of alpha-methyl-5-hydroxytryptophan". Eur J Pharmacol. 8 (3): 292–295. doi:10.1016/0014-2999(69)90037-5. PMID 5308817.
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