Didesmethylsibutramine

Didesmethylsibutramine
Identifiers
	IUPAC name 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutan-1-amine;
CAS Number	84467-54-9 ;
PubChem CID	134772;
ChemSpider	118777;
CompTox Dashboard (EPA)	DTXSID801004734 ;
ECHA InfoCard	100.125.498
Chemical and physical data
Formula	C16H24ClN
Molar mass	265.83 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC(C)CC(C1(CCC1)C2=CC=C(C=C2)Cl)N;
	InChI InChI=1S/C15H22ClN/c1-11(2)10-14(17)15(8-3-9-15)12-4-6-13(16)7-5-12/h4-7,11,14H,3,8-10,17H2,1-2H3; Key:WQSACWZKKZPCHN-UHFFFAOYSA-N;

Didesmethylsibutramine (Dinorsibutramine , Bisnorsibutramine, BTS-54524) is an active metabolite of the anorectic drug sibutramine that has been identified as an adulterant in weight loss supplements.^[1]^[2] Data on the activity of didesmethylsibutramine in humans is limited, although a case of psychosis associated with didesmethylsibutramine use was reported in 2019.^[3]

Pharmacology

**MAT** Affinity (K_i nM)^[4]
	SERTTooltip Serotonin transporter	NETTooltip Norepinephrine transporter	DATTooltip Dopamine transporter
Racemate	20	15	45
(R)	140	13	8.9
(S)	4,300	62	12

Didesmethylsibutramine acts as a triple reuptake inhibitor, blocking the reabsorption of serotonin, dopamine, and norepinephrine from neuronal synapses.^[5] The (R)-enantiomer of didesmethylsibutramine is a more potent inhibitor of monoamine reuptake than the (S)-enantiomer and possesses significantly stronger anorectic activity in animals.^[6]

Pharmacokinetics

Following sibutramine administration in humans, didesmethylsibutramine (M2) is formed through the n-demethylation of desmethylsibutramine (M1) by CYP2B6.^[7] Elevated plasma levels of sibutramine are observed with concomitant use of CYP2B6 inhibitors (e.g. clopidogrel) and in individuals with certain CYP2B6 genotypes due to the reduced conversion of sibutramine into desmethylsibutramine.^[8]^[9]

References

^ Kozhuharov VR, Ivanov K, Ivanova S (22 April 2022). "Dietary Supplements as Source of Unintentional Doping". BioMed Research International. 2022: 8387271. doi:10.1155/2022/8387271. PMC 9054437. PMID 35496041.
^ Kim HJ, Lee JH, Park HJ, Cho SH, Cho S, Kim WS (4 May 2014). "Monitoring of 29 weight loss compounds in foods and dietary supplements by LC-MS/MS". Food Additives & Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment. 31 (5): 777–783. doi:10.1080/19440049.2014.888497. PMID 24499058. S2CID 31818942.
^ Kim MD, Seo JS, Jon DI, Lee KH, Bahk WM, Kwon YJ (9 April 2019). "T64. Two Cases of Brief Affective Psychosis Induced by Diet Aids". Schizophrenia Bulletin. 45 (Supplement_2): S228–S229. doi:10.1093/schbul/sbz019.344. PMC 6455467.
^ Rothman RB, Baumann MH (May 2009). "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety. 8 (3): 317–329. doi:10.1517/14740330902931524. PMC 2695569. PMID 19505264.
^ Nisoli E, Carruba MO (October 2000). "An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action". Obesity Reviews. 1 (2): 127–139. doi:10.1046/j.1467-789x.2000.00020.x. PMID 12119986. S2CID 20553857.
^ Glick SD, Haskew RE, Maisonneuve IM, Carlson JN, Jerussi TP (May 2000). "Enantioselective behavioral effects of sibutramine metabolites". European Journal of Pharmacology. 397 (1): 93–102. doi:10.1016/S0014-2999(00)00216-8. PMID 10844103.
^ Bae SK, Cao S, Seo KA, Kim H, Kim MJ, Shon JH, et al. (August 2008). "Cytochrome P450 2B6 catalyzes the formation of pharmacologically active sibutramine (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) metabolites in human liver microsomes". Drug Metabolism and Disposition. 36 (8): 1679–1688. doi:10.1124/dmd.108.020727. PMID 18474675. S2CID 206495548.
^ Bae JW, Jang CG, Lee SY (December 2011). "Effects of clopidogrel on the pharmacokinetics of sibutramine and its active metabolites". Journal of Clinical Pharmacology. 51 (12): 1704–1711. doi:10.1177/0091270010388651. PMID 21209232. S2CID 121878.
^ Pan W, Bae SK, Shim EJ, Park SE, Lee SS, Park SJ, et al. (February 2013). "Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 43 (2): 211–218. doi:10.3109/00498254.2012.706722. PMID 22830954. S2CID 25985390.

[1] Kozhuharov VR, Ivanov K, Ivanova S (22 April 2022). "Dietary Supplements as Source of Unintentional Doping". BioMed Research International. 2022: 8387271. doi:10.1155/2022/8387271. PMC 9054437. PMID 35496041.

[2] Kim HJ, Lee JH, Park HJ, Cho SH, Cho S, Kim WS (4 May 2014). "Monitoring of 29 weight loss compounds in foods and dietary supplements by LC-MS/MS". Food Additives & Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment. 31 (5): 777–783. doi:10.1080/19440049.2014.888497. PMID 24499058. S2CID 31818942.

[3] Kim MD, Seo JS, Jon DI, Lee KH, Bahk WM, Kwon YJ (9 April 2019). "T64. Two Cases of Brief Affective Psychosis Induced by Diet Aids". Schizophrenia Bulletin. 45 (Supplement_2): S228–S229. doi:10.1093/schbul/sbz019.344. PMC 6455467.

[pmid19505264-4] Rothman RB, Baumann MH (May 2009). "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety. 8 (3): 317–329. doi:10.1517/14740330902931524. PMC 2695569. PMID 19505264.

[pmid12119986-5] Nisoli E, Carruba MO (October 2000). "An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action". Obesity Reviews. 1 (2): 127–139. doi:10.1046/j.1467-789x.2000.00020.x. PMID 12119986. S2CID 20553857.

[6] Glick SD, Haskew RE, Maisonneuve IM, Carlson JN, Jerussi TP (May 2000). "Enantioselective behavioral effects of sibutramine metabolites". European Journal of Pharmacology. 397 (1): 93–102. doi:10.1016/S0014-2999(00)00216-8. PMID 10844103.

[7] Bae SK, Cao S, Seo KA, Kim H, Kim MJ, Shon JH, et al. (August 2008). "Cytochrome P450 2B6 catalyzes the formation of pharmacologically active sibutramine (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) metabolites in human liver microsomes". Drug Metabolism and Disposition. 36 (8): 1679–1688. doi:10.1124/dmd.108.020727. PMID 18474675. S2CID 206495548.

[8] Bae JW, Jang CG, Lee SY (December 2011). "Effects of clopidogrel on the pharmacokinetics of sibutramine and its active metabolites". Journal of Clinical Pharmacology. 51 (12): 1704–1711. doi:10.1177/0091270010388651. PMID 21209232. S2CID 121878.

[9] Pan W, Bae SK, Shim EJ, Park SE, Lee SS, Park SJ, et al. (February 2013). "Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 43 (2): 211–218. doi:10.3109/00498254.2012.706722. PMID 22830954. S2CID 25985390.

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Pharmacology

Pharmacokinetics

See also

References