Esmethadone

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 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]

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

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 (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