en Triazoledione

Triazoledione
Clinical data
Other names	BMS-180492
Pharmacokinetic data
Elimination half-life	18 hours
Identifiers
	IUPAC name 1-[3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl]-4-(2-phenoxyethyl)-1,2,4-triazolidine-3,5-dione;
CAS Number	153707-88-1;
PubChem CID	9804174;
ChemSpider	7979934;
UNII	3508097W2U;
ChEMBL	ChEMBL1598729;
CompTox Dashboard (EPA)	DTXSID701122505 ;
Chemical and physical data
Formula	C23H28ClN5O3
Molar mass	457.96 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CN(CCN1CCCN2C(=O)N(C(=O)N2)CCOC3=CC=CC=C3)C4=CC(=CC=C4)Cl;
	InChI InChI=1S/C23H28ClN5O3/c24-19-6-4-7-20(18-19)27-14-12-26(13-15-27)10-5-11-29-23(31)28(22(30)25-29)16-17-32-21-8-2-1-3-9-21/h1-4,6-9,18H,5,10-17H2,(H,25,30); Key:BTNXVMLCKOPOEP-UHFFFAOYSA-N;

Triazoledione (developmental code name BMS-180492) is a phenylpiperazine compound and a major metabolite of the antidepressant nefazodone.^[2]^[3] It is active, but with substantially reduced potency compared to nefazodone (approximately one-seventh).^[3]^[2] As such, it has been suggested that it is unlikely that triazoledione contributes significantly to the pharmacology of nefazodone.^[3] However, triazoledione may reach concentrations as great as 10 times those of nefazodone, and hence could still be a significant contributor to its therapeutic effects.^[2]

Pharmacology

Triazoledione^[4]^[5]^[3]
Site	K_i (nM)	Species	Ref
SERTTooltip Serotonin transporter	≥34,527 ≥26,471	Human Rat	^[5] ^[5]^[3]
NETTooltip Norepinephrine transporter	>100,000 100,000	Human Rat	^[5]
DATTooltip Dopamine transporter	ND	ND	ND
5-HT_1A	636–1,371	Rat	^[3]^[5]
5-HT_2A	159–211	Rat	^[5]^[3]
5-HT_2C	ND	ND	ND
α₁	173 1,000	Human Rat	^[5] ^[3]
α₂	1,915 1,000	Human Rat	^[5] ^[3]
β	>100,000	Rat	^[3]
H₁	11	Guinea pig	^[5]
mAChTooltip Muscarinic acetylcholine receptor	>100,000	Rat	^[5]
Values are K_i (nM). The smaller the value, the more strongly the drug binds to the site.

Triazoledione shows significant affinity for the serotonin 5-HT_1A and 5-HT_2A receptors, the α₁-adrenergic receptor, and the histamine H₁ receptor.^[3]^[5] It shows negligible affinity for the serotonin and norepinephrine transporters and the muscarinic acetylcholine receptors.^[3]^[5]

Comparison of binding profiles of triazoledione and related compounds^[3]^[5]
Compound	5-HT_1A	5-HT_2A	SERTTooltip Serotonin transporter	NETTooltip Norepinephrine transporter	α₁	α₂	β	H₁	mAChTooltip Muscarinic acetylcholine receptor
Hydroxynefazodone	56–589	7.2–34	165–1,203	376–1,053	8.0–145	63–2,490	>1,000	28	11,357
mCPPTooltip meta-Chlorophenylpiperazine	16–411	110–433	127–432	490–4,360	97–763	112–371	4,890	449	4,702
Nefazodone	52–1,030	7.1–32	181–549	200–713	5.5–144	84–41,700	>100,000	30	4,569
Trazodone	42–288	11–20	115–690	≥20,887	12–23	106–1,070	47,100	29	12,188
Triazoledione	636–1,371	159–211	≥26,471	>100,000	≥173	≥1,915	>100,000	11	>100,000
Values are K_i (nM). The smaller the value, the more strongly the drug binds to the site.

References

^ Golden RN, Dawkins K, Nicholas L (2017). "Trazodone and Nefazodone". In Schatzberg AF, Nemeroff CB (eds.). The American Psychiatric Association Publishing Textbook of Psychopharmacology (Fifth ed.). American Psychiatric Pub. pp. 460–. ISBN 978-1-58562-523-9.
^ ^a ^b ^c Preskorn SH, Catterson ML (6 December 2012). "General Principles of Pharmacokinetics". In Preskorn SH, Stanga CY, Feighner JP, Ross R (eds.). Antidepressants: Past, Present and Future. Springer Science & Business Media. pp. 68–. ISBN 978-3-642-18500-7.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Davis R, Whittington R, Bryson HM (April 1997). "Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression". Drugs. 53 (4): 608–636. doi:10.2165/00003495-199753040-00006. PMID 9098663. S2CID 239077479.
^ Roth BL, Driscol J. "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (December 1997). "Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites". The Journal of Pharmacology and Experimental Therapeutics. 283 (3): 1305–1322. PMID 9400006.

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[SchatzbergNemeroff2017-1] Golden RN, Dawkins K, Nicholas L (2017). "Trazodone and Nefazodone". In Schatzberg AF, Nemeroff CB (eds.). The American Psychiatric Association Publishing Textbook of Psychopharmacology (Fifth ed.). American Psychiatric Pub. pp. 460–. ISBN 978-1-58562-523-9.

[PreskornStanga2012-2] Preskorn SH, Catterson ML (6 December 2012). "General Principles of Pharmacokinetics". In Preskorn SH, Stanga CY, Feighner JP, Ross R (eds.). Antidepressants: Past, Present and Future. Springer Science & Business Media. pp. 68–. ISBN 978-3-642-18500-7.

[pmid9098663-3] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Davis R, Whittington R, Bryson HM (April 1997). "Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression". Drugs. 53 (4): 608–636. doi:10.2165/00003495-199753040-00006. PMID 9098663. S2CID 239077479.

[PDSP-4] Roth BL, Driscol J. "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.

[pmid9400006-5] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (December 1997). "Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites". The Journal of Pharmacology and Experimental Therapeutics. 283 (3): 1305–1322. PMID 9400006.

[1]

[2]

[3]

[4]

[5]

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Triazoledione

Pharmacology

See also

References

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