Jump to content

LY-116467

Add links
From Wikipedia, the free encyclopedia

LY-116467
Clinical data
Other namesLY116467; LY-116,467; LY-062; LY062; 6-Methylpergolide; 6-Methyl-pergolide; 6-Methyl-8β-((methylthio)methyl)ergoline
Drug classDopamine receptor agonist; Serotonin receptor modulator
ATC code
  • None
Identifiers
  • (6aR,9R,10aR)-7-methyl-9-(methylsulfanylmethyl)-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline
PubChem CID
ChemSpider
Chemical and physical data
FormulaC17H22N2S
Molar mass286.44 g·mol−1
3D model (JSmol)
  • CN1C[C@@H](C[C@H]2[C@H]1CC3=CNC4=CC=CC2=C34)CSC
  • InChI=1S/C17H22N2S/c1-19-9-11(10-20-2)6-14-13-4-3-5-15-17(13)12(8-18-15)7-16(14)19/h3-5,8,11,14,16,18H,6-7,9-10H2,1-2H3/t11-,14-,16-/m1/s1
  • Key:HEZLHSNBFOCKCQ-DJSGYFEHSA-N

LY-116467, also known as LY-062, 6-methylpergolide, or 6-methyl-8β-((methylthio)methyl)ergoline, is a dopamine receptor agonist of the ergoline family which was never marketed.[1][2] It is the analogue of the antiparkinsonian agent pergolide in which the propyl group at the 6 position has been replaced with a methyl group.[1][2]

The drug shows high affinity for the dopamine D2 receptor (Ki = 12 nM), where it acts as a potent full agonist with similar potency and efficacy as pergolide (EC50Tooltip half-maximal effective concentration = 14.5–16.2 nM; EmaxTooltip maximal efficacy = 90–97%).[2][3] In addition to its dopamine receptor agonism, LY-116467 also shows high affinity for serotonin 5-HT1 and 5-HT2 receptors (K0.5 = 7.7 nM and Ki = 70 nM, respectively)[2] as well as affinity for the α1- and α2-adrenergic receptors.[4][5]

Compared to pergolide, LY-116467 showed 3.4-fold lower affinity for the dopamine D2 receptor, 4-fold higher affinity for the serotonin 5-HT1 receptor, and 1.3-fold lower affinity for the serotonin 5-HT2 receptor.[2] The drug is similarly or less potent as a dopamine receptor agonist than pergolide in vivo.[1] Whereas pergolide is a potent serotonin 5-HT2A and 5-HT2B receptor partial agonist, LY-116467 instead acted as a potent silent antagonist of these receptors.[3][6] The drug is a weak antagonist of the α1- and α2-adrenergic receptors similarly to pergolide.[5]

LY-116467 was first described in the scientific literature by 1982.[7][1] It has been suggested that LY-116467 may lack the cardiac valvulopathy of pergolide and could be used clinically as a non-cardiotoxic replacement for it.[3][8]

See also

[edit]

References

[edit]
  1. 1 2 3 4 Fuller RW, Snoddy HD, Mason NR, Clemens JA, Bemis KG (1983). "Elevation of serum corticosterone in rats by dopamine agonists related in structure to pergolide". Neuroendocrinology. 36 (4): 285–290. doi:10.1159/000123469. PMID 6866215.
  2. 1 2 3 4 5 Beart PM, McDonald D, Cincotta M, de Vries DJ, Gundlach AL (1986). "Selectivity of some ergot derivatives for 5-HT1 and 5-HT2 receptors of rat cerebral cortex". General Pharmacology. 17 (1): 57–62. doi:10.1016/0306-3623(86)90011-x. PMID 3949149.
  3. 1 2 3 Görnemann T, Hübner H, Gmeiner P, Horowski R, Latté KP, Flieger M, et al. (March 2008). "Characterization of the molecular fragment that is responsible for agonism of pergolide at serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A receptors". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 1136–1145. doi:10.1124/jpet.107.133165. PMID 18096760.
  4. ↑ McPherson GA, Beart PM (August 1983). "The selectivity of some ergot derivatives for alpha 1 and alpha 2-adrenoceptors of rat cerebral cortex". European Journal of Pharmacology. 91 (4): 363–369. doi:10.1016/0014-2999(83)90159-0. PMID 6311586.
  5. 1 2 McPherson GA (January 1984). "In vitro selectivity of lisuride and other ergot derivatives for alpha 1- and alpha 2-adrenoceptors". European Journal of Pharmacology. 97 (1–2): 151–155. doi:10.1016/0014-2999(84)90525-9. PMID 6321208.
  6. ↑ Dosa PI, Ward T, Walters MA, Kim SW (February 2013). "Synthesis of novel analogs of cabergoline: improving cardiovascular safety by removing 5-HT2B receptor agonism". ACS Medicinal Chemistry Letters. 4 (2): 254–258. doi:10.1021/ml3003814. PMC 3629922. PMID 23606928.
  7. ↑ Gundlach AL, McDonald D, Beart PM (September 1982). "[3H]Spiperone labels non-cyclase-linked dopamine receptors in the ventral tegmental area of rat brain". Journal of Neurochemistry. 39 (3): 890–894. doi:10.1111/j.1471-4159.1982.tb07978.x. PMID 7097294.
  8. ↑ Dosa PI, Amin EA (February 2016). "Tactical Approaches to Interconverting GPCR Agonists and Antagonists". Journal of Medicinal Chemistry. 59 (3): 810–840. doi:10.1021/acs.jmedchem.5b00982. PMID 26390077.
Retrieved from "https://en.wikipedia.org/w/index.php?title=LY-116467&oldid=1370680723"