Esmethadone

Esmethadone

Clinical data
Other names	Dextromethadone; d-Methadone; 6S-Methadone; (+)-Methadone
Identifiers
IUPAC name (6S)-6-(Dimethylamino)-4,4-diphenylheptan-3-one
CAS Number	5653-80-5
PubChem CID	643985
ChemSpider	559067
UNII	S95RZH8AMH
ChEBI	CHEBI:167308
CompTox Dashboard (EPA)	DTXSID501045751
ECHA InfoCard	100.164.915
Chemical and physical data
Formula	C21H27NO
Molar mass	309.453 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCC(=O)C(C[C@H](C)N(C)C)(C1=CC=CC=C1)C2=CC=CC=C2
InChI 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 (INN Tooltip 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 was under development for the treatment of major depressive disorder. ^[4] As of December 2024, phase 3 clinical trials for this indication were discontinued due to the potential of eye disorders, mitochondrial disorders, neuropathic pain and Rett syndrome. ^[4]

There is an asymmetric synthesis available to prepare both esmethadone (S-(+)-methadone) and levomethadone (R-(−)-methadone). ^{[5] [6]}

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Receptor binding affinities of isomers of methadone ^{[3] [1]}

Compound	Affinities (Ki Tooltip Inhibitor constant, in nM)						Ratios
	MOR Tooltip μ-Opioid receptor	DOR Tooltip δ-Opioid receptor	KOR Tooltip κ-Opioid receptor	SERT Tooltip Serotonin transporter	NET Tooltip Norepinephrine transporter	NMDAR Tooltip 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. 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. 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. "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. USpatent 6143933  

https://seekingalpha.com/article/4679773?gt=007e6ed9bf2fefc2