Triazoledione

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]

Triazoledione

Clinical data
Other names	BMS-180492
Pharmacokinetic data
Elimination half-life	18 hours[1]
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

Pharmacology

Triazoledione^[4][5][3]

Site	Ki (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-HT1A	636–1,371	Rat	[3][5]
5-HT2A	159–211	Rat	[5][3]
5-HT2C	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 Ki (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-HT1A	5-HT2A	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 Ki (nM). The smaller the value, the more strongly the drug binds to the site.

See also

• Serotonin antagonist and reuptake inhibitor

References

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.
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.
3. 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.
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.
5. 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.