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LY-53,857

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LY-53857
Clinical data
Other namesLY53857; LY-53,857; 6-Methyl-1-(1-methylethyl)ergoline-8β-carboxylic acid 2-hydroxy-1-methylpropyl ester
Drug classSerotonin 5-HT2 receptor antagonist; Serotonin 5-HT2A receptor antagonist; Serotonin 5-HT2B receptor antagonist; Serotonin 5-HT2C receptor antagonist; Serotonin 5-HT7 receptor antagonist
ATC code
  • None
Identifiers
  • 3-hydroxybutan-2-yl (6aR,9R,10aR)-7-methyl-4-propan-2-yl-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-9-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC23H32N2O3
Molar mass384.520 g·mol−1
3D model (JSmol)
  • CC(C)N1C=C2C[C@@H]3[C@H](C[C@H](CN3C)C(=O)OC(C)C(C)O)C4=C2C1=CC=C4
  • InChI=1S/C23H32N2O3/c1-13(2)25-12-16-10-21-19(18-7-6-8-20(25)22(16)18)9-17(11-24(21)5)23(27)28-15(4)14(3)26/h6-8,12-15,17,19,21,26H,9-11H2,1-5H3/t14?,15?,17-,19-,21-/m1/s1
  • Key:JQYLIGHHVGCTPR-LYRPIDSHSA-N

LY-53857 is a serotonin 5-HT2 receptor antagonist of the ergoline family which has been widely used in scientific research.[1][2][3][4]

It is a potent antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors (Ki = 7.2–50 nM, 6.3–6.9 nM, and 7.9–8.3 nM, respectively).[1][5][6][7][8][9] The drug shows strong selectivity for the serotonin 5-HT2 receptors over the serotonin 5-HT1 and α-adrenergic receptors.[10] Although originally thought to be selective for the serotonin 5-HT2 receptors,[1] LY-53857 was subsequently found to also show significant affinity for the serotonin 5-HT7 receptor (Ki = 100 nM), where it is likewise an antagonist.[11][12] In addition, it shows high affinity for the serotonin 5-HT1F receptor (Ki = 6.87 nM).[13]

It produces antidepressant-like and anxiolytic-like effects in rodents.[3][14][15][16][17][18] The drug has no effect on locomotor activity by itself, but blocks the hyperlocomotion induced by phencyclidine (PCP).[19] In addition, whereas meta-chlorophenylpiperazine (mCPP) produces hypolocomotion by itself, the combination of mCPP with LY-53857 results in mCPP producing hyperlocomotion instead.[20][21] LY-53857 blocks the discriminative stimulus of the psychedelic drugs LSD, mescaline, and DOM in rodent drug discrimination studies.[9][22][23][24] The drug inhibits the hyperthermia induced by the psychedelic drug DOI, by mCPP, and by the serotonin releasing agent para-chloroamphetamine (PCA).[25][26][27]

Analogues of LY-53857 have also been described and include LY-86057 (the N1-desisopropyl analogue), LY-108742 (the N1-methyl analogue), and LY-197541 (the N1-isobutyl analogue).[28][4][29]

LY-53857 was first described in the scientific literature by 1979.[30]

See also

References

  1. Barnes NM, Sharp T (August 1999). "A review of central 5-HT receptors and their function". Neuropharmacology. 38 (8): 1083–1152. doi:10.1016/s0028-3908(99)00010-6. PMID 10462127.
  2. Cohen ML, Fuller RW, Kurz KD (November 1983). "LY53857, a selective and potent serotonergic (5-HT2) receptor antagonist, does not lower blood pressure in the spontaneously hypertensive rat". The Journal of Pharmacology and Experimental Therapeutics. 227 (2): 327–332. PMID 6313898.
  3. Hingtgen JN, Fuller RW, Mason NR, Aprison MH (June 1985). "Blockade of a 5-hydroxytryptophan-induced animal model of depression with a potent and selective 5-HT2 receptor antagonist (LY53857)". Biological Psychiatry. 20 (6): 592–597. doi:10.1016/0006-3223(85)90093-9. PMID 3873259.
  4. Nelson DL, Lucaites VL, Audia JE, Nissen JS, Wainscott DB (June 1993). "Species differences in the pharmacology of the 5-hydroxytryptamine2 receptor: structurally specific differentiation by ergolines and tryptamines". The Journal of Pharmacology and Experimental Therapeutics. 265 (3): 1272–1279. PMID 8510008.
  5. van Wijngaarden I, Soudijn W (1997). "5-HT2A, 5-HT2B and 5-HT2C receptor ligands". Pharmacochemistry Library. Vol. 27. Elsevier. pp. 161–197. doi:10.1016/s0165-7208(97)80013-x. ISBN 978-0-444-82041-9.
  6. Sahin-Erdemli I, Schoeffter P, Hoyer D (August 1991). "Competitive antagonism by recognized 5-HT2 receptor antagonists at 5-HT1C receptors in pig choroid plexus". Naunyn-Schmiedeberg's Archives of Pharmacology. 344 (2): 137–142. doi:10.1007/BF00167210. PMID 1944609.
  7. Baxter GS, Murphy OE, Blackburn TP (May 1994). "Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle". British Journal of Pharmacology. 112 (1): 323–331. doi:10.1111/j.1476-5381.1994.tb13072.x. PMC 1910288. PMID 8032658.
  8. Glusa E, Pertz HH (June 2000). "Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT(2B) receptors". British Journal of Pharmacology. 130 (3): 692–698. doi:10.1038/sj.bjp.0703341. PMC 1572101. PMID 10821800.
  9. Fiorella D, Rabin RA, Winter JC (October 1995). "The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis". Psychopharmacology. 121 (3). Berl: 347–356. doi:10.1007/BF02246074. PMID 8584617.
  10. Cohen ML, Kurz KD, Mason NR, Fuller RW, Marzoni GP, Garbrecht WL (November 1985). "Pharmacological activity of the isomers of LY53857, potent and selective 5-HT2 receptor antagonists". The Journal of Pharmacology and Experimental Therapeutics. 235 (2): 319–323. PMID 4057073.
  11. Lopez-Rodriguez M, Benhamu B, Morcillo M, Porras E, Lavandera J, Pardo L (1 September 2004). "Serotonin 5-HT7 Receptor Antagonists". Current Medicinal Chemistry-Central Nervous System Agents. 4 (3): 203–214. doi:10.2174/1568015043356931.
  12. Cushing DJ, Zgombick JM, Nelson DL, Cohen ML (June 1996). "LY215840, a high-affinity 5-HT7 receptor ligand, blocks serotonin-induced relaxation in canine coronary artery". The Journal of Pharmacology and Experimental Therapeutics. 277 (3): 1560–1566. PMID 8667223.
  13. Wainscott DB, Cohen ML, Schenck KW, Audia JE, Nissen JS, Baez M, et al. (March 1993). "Pharmacological characteristics of the newly cloned rat 5-hydroxytryptamine2F receptor". Mol Pharmacol. 43 (3): 419–426. PMID 8450835.
  14. Kennett GA (1992). "5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction model". Psychopharmacology. 107 (2–3). Berl: 379–384. doi:10.1007/BF02245165. PMID 1352056.
  15. Kennett GA, Pittaway K, Blackburn TP (February 1994). "Evidence that 5-HT2c receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety". Psychopharmacology. 114 (1). Berl: 90–96. doi:10.1007/BF02245448. PMID 7846211.
  16. Yamada J, Sugimoto Y (September 2001). "Effects of 5-HT(2) receptor antagonists on the anti-immobility effects of imipramine in the forced swimming test with mice". European Journal of Pharmacology. 427 (3): 221–225. doi:10.1016/s0014-2999(01)01240-7. PMID 11567652.
  17. Sugimoto Y, Yamada S, Yamada J (November 2002). "The 5-HT2 receptor antagonist reduces immobility of mice treated with the atypical antidepressant mianserin in the forced swimming test". Biological & Pharmaceutical Bulletin. 25 (11): 1479–1481. doi:10.1248/bpb.25.1479. PMID 12419964.
  18. Yamada J, Sugimoto Y (December 2002). "Differential effects of the 5-HT2 receptor antagonist on the anti-immobility effects of noradrenaline and serotonin reuptake inhibitors in the forced swimming test". Brain Research. 958 (1): 161–165. doi:10.1016/s0006-8993(02)03684-3. PMID 12468041.
  19. Gleason SD, Shannon HE (January 1997). "Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice". Psychopharmacology. 129 (1). Berl: 79–84. doi:10.1007/s002130050165. PMID 9122367.
  20. Gleason SD, Shannon HE (January 1998). "Meta-chlorophenylpiperazine induced changes in locomotor activity are mediated by 5-HT1 as well as 5-HT2C receptors in mice". European Journal of Pharmacology. 341 (2–3): 135–138. doi:10.1016/s0014-2999(97)01474-x. PMID 9543230.
  21. Gleason SD, Lucaites VL, Shannon HE, Nelson DL, Leander JD (December 2001). "m-CPP hypolocomotion is selectively antagonized by compounds with high affinity for 5-HT(2C) receptors but not 5-HT(2A) or 5-HT(2B) receptors". Behavioural Pharmacology. 12 (8): 613–620. doi:10.1097/00008877-200112000-00005. PMID 11856898.
  22. Cunningham KA, Appel JB (1987). "Neuropharmacological reassessment of the discriminative stimulus properties of d-lysergic acid diethylamide (LSD)". Psychopharmacology. 91 (1). Berl: 67–73. doi:10.1007/BF00690929. PMID 3103161.
  23. Appel JB, Callahan PM (January 1989). "Involvement of 5-HT receptor subtypes in the discriminative stimulus properties of mescaline". European Journal of Pharmacology. 159 (1): 41–46. doi:10.1016/0014-2999(89)90041-1. PMID 2707301.
  24. Glennon RA, Hauck AE (December 1985). "Mechanistic studies on DOM as a discriminative stimulus". Pharmacology, Biochemistry, and Behavior. 23 (6): 937–941. doi:10.1016/0091-3057(85)90096-6. PMID 2934750.
  25. Mazzola-Pomietto P, Aulakh CS, Wozniak KM, Hill JL, Murphy DL (January 1995). "Evidence that 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia in rats is mediated by stimulation of 5-HT2A receptors". Psychopharmacology. 117 (2). Berl: 193–199. doi:10.1007/BF02245187. PMID 7753967.
  26. Mazzola-Pomietto P, Aulakh CS, Wozniak KM, Murphy DL (February 1996). "Evidence that m-chlorophenylpiperazine-induced hyperthermia in rats is mediated by stimulation of 5-HT2C receptors". Psychopharmacology. 123 (4). Berl: 333–339. doi:10.1007/BF02246643. PMID 8867872.
  27. Sugimoto Y, Ohkura M, Inoue K, Yamada J (September 2000). "Involvement of the 5-HT(2) receptor in hyperthermia induced by p-chloroamphetamine, a serotonin-releasing drug in mice". European Journal of Pharmacology. 403 (3): 225–228. doi:10.1016/s0014-2999(00)00585-9. PMID 10973623.
  28. Johnson MP, Audia JE, Nissen JS, Nelson DL (August 1993). "N(1)-substituted ergolines and tryptamines show species differences for the agonist-labeled 5-HT2 receptor". Eur J Pharmacol. 239 (1–3): 111–118. doi:10.1016/0014-2999(93)90983-o. PMID 8223886.
  29. Johnson MP, Loncharich RJ, Baez M, Nelson DL (February 1994). "Species variations in transmembrane region V of the 5-hydroxytryptamine type 2A receptor alter the structure-activity relationship of certain ergolines and tryptamines". Mol Pharmacol. 45 (2): 277–286. doi:10.1016/S0026-895X(25)09924-9. PMID 8114677.
  30. Fuller RW, Snoddy HD (October 1979). "The effects of metergoline and other serotonin receptor antagonists on serum corticosterone in rats". Endocrinology. 105 (4): 923–928. doi:10.1210/endo-105-4-923. PMID 477605.