Esmethadone

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Esmethadone
File:Dextromethadone structure.svg
Clinical data
Other namesDextromethadone; d-Methadone; 6S-Methadone; (+)-Methadone
Identifiers
  • (6S)-6-(Dimethylamino)-4,4-diphenylheptan-3-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
Chemical and physical data
FormulaC21H27NO
Molar mass309.453 g·mol−1
3D model (JSmol)
  • CCC(=O)C(C[C@H](C)N(C)C)(C1=CC=CC=C1)C2=CC=CC=C2
  • InChI=1S/C21H27NO/c1-5-20(23)21(16-17(2)22(3)4,18-12-8-6-9-13-18)19-14-10-7-11-15-19/h6-15,17H,5,16H2,1-4H3/t17-/m0/s1
  • Key:USSIQXCVUWKGNF-KRWDZBQOSA-N

Esmethadone (INNTooltip International Nonproprietary Name; developmental code name REL-1017), also known as dextromethadone, is the (S)-enantiomer of methadone. It acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist, among other actions.[1] Unlike levomethadone, it has low affinity for opioid receptors and lacks significant respiratory depressant action and abuse liability.[2][3] Esmethadone is under development for the treatment of major depressive disorder.[4] As of August 2022, it is in phase 3 clinical trials for this indication.[4] There is an asymmetric synthesis available to prepare both esmethadone (S-(+)-methadone) and levomethadone (R-(−)-methadone).[5][6]

Receptor binding affinities of isomers of methadone[3][1]
Compound Affinities (KiTooltip Inhibitor constant, in nM) Ratios
MORTooltip μ-Opioid receptor DORTooltip δ-Opioid receptor KORTooltip κ-Opioid receptor SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter NMDARTooltip N-Methyl-D-aspartate receptor M:D:K SERT:NET
Racemic methadone 1.7 435 405 1,400 259 2,500–8,300 1:256:238 1:5
Dextromethadone 19.7 960 1,370 992 12,700 2,600–7,400 1:49:70 1:13
Levomethadone 0.945 371 1,860 14.1 702 2,800–3,400 1:393:1968 1:50

References

  1. ↑ 1.0 1.1 Gorman AL, Elliott KJ, Inturrisi CE (February 1997). "The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord". Neurosci. Lett. 223 (1): 5–8. doi:10.1016/S0304-3940(97)13391-2. PMID 9058409.
  2. ↑ "METHADONE" (PDF). Drug & Chemical Evaluation Section. Drug Enforcement Agency. Retrieved 14 November 2020.
  3. ↑ 3.0 3.1 Codd EE, Shank RP, Schupsky JJ, Raffa RB (1995). "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". J. Pharmacol. Exp. Ther. 274 (3): 1263–70. PMID 7562497.
  4. ↑ 4.0 4.1 "Dextromethadone - Cornell University/Relmada Therapeutics - AdisInsight".
  5. ↑ Hull JD, Scheinmann F, Turner NJ (March 2003). "Synthesis of optically active methadones, LAAM and bufuralol by lipase-catalysed acylations". Tetrahedron: Asymmetry. 14 (5): 567–576. doi:10.1016/S0957-4166(03)00019-3.
  6. ↑ US patent 6143933 
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