Donitriptan

Donitriptan (INNTooltip International Nonproprietary Name; developmental code name F-11356) is a triptan drug which was investigated as an antimigraine agent but was never marketed.^[1][2][3] It acts as a selective serotonin 5-HT_1B and 5-HT_1D receptor agonist.^[4][5][6][3] The drug reached phase 2 clinical trials prior to the discontinuation of its development.^[7]

Donitriptan

Clinical data
Other names	F-11356; F11356; F-12640; F12640
Drug class	Serotonin 5-HT1B and 5-HT1D receptor agonist; Antimigraine agent; Triptan
ATC code	None
Legal status
Legal status	Never marketed
Identifiers
IUPAC name 4-[4-({[3-(2-Aminoethyl)-1H-indol-5-yl]oxy}acetyl)-1-piperazinyl]benzonitrile
CAS Number	170912-52-4
PubChem CID	197706
ChemSpider	171128
UNII	70968BVH2J
ChEMBL	ChEMBL1742428
CompTox Dashboard (EPA)	DTXSID20168974
Chemical and physical data
Formula	C23H25N5O2
Molar mass	403.486 g·mol−1
3D model (JSmol)	Interactive image
SMILES c1cc(ccc1C#N)N2CCN(CC2)C(=O)COc3ccc4c(c3)c(c[nH]4)CCN
InChI InChI=1S/C23H25N5O2/c24-8-7-18-15-26-22-6-5-20(13-21(18)22)30-16-23(29)28-11-9-27(10-12-28)19-3-1-17(14-25)2-4-19/h1-6,13,15,26H,7-12,16,24H2 Key:SOHCKWZVTCTQBG-UHFFFAOYSA-N

Pharmacology

Donitriptan activities

Target	Affinity (Ki, nM)
5-HT1A	12–25 (Ki) 182–1,150 (EC50Tooltip half-maximal effective concentration)
5-HT1B	0.08–0.36 (Ki) 0.10–1.8 (EC50) 94–100% (EmaxTooltip maximal efficacy)
5-HT1D	0.06–0.48 (Ki) 0.27–0.83 (EC50) 97–99% (Emax)
5-HT1E	1,150–1,700 (Ki) >10,000 (EC50)
5-HT1F	3,390–6,610 (Ki) >10,000 (EC50)
5-HT2A	182–447 (Ki) 7.9 (EC50)
5-HT2B	813 (Ki) 25 (EC50)
5-HT2C	575 (Ki) (rat) ND (EC50)
5-HT3	>10,000 (mouse)
5-HT4	2,000 (guinea pig)
5-HT5A	813
5-HT6	2,340
5-HT7	372–617 (Ki) 5,890 (EC50)
α1A–α1D	ND
α2A–α2C	ND
β1–β3	ND
D1	>10,000
D2	>10,000
D3–D5	ND
H1	>10,000
H2	>10,000
H3, H4	ND
M1–M5	ND
mACh	>10,000
I1, I2	>1,000
σ1, σ2	ND
TAAR1Tooltip Trace amine-associated receptor 1	ND
SERTTooltip Serotonin transporter	>1,000 (IC50Tooltip half-maximal inhibitory concentration)
NETTooltip Norepinephrine transporter	>1,000 (IC50)
DATTooltip Dopamine transporter	>1,000 (IC50)
MAO-ATooltip Monoamine oxidase A	>10,000
MAO-BTooltip Monoamine oxidase B	>10,000
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [4][5][8][9][6][3]

Donitriptan acts as a high-affinity, high-efficacy near-full agonist of the serotonin 5-HT_1B (K_i = 0.079–0.40 nM; E_maxTooltip maximal efficacy = 94%) and 5-HT_1D receptors (K_i = 0.063–0.50 nM; E_max = 97%), and is among the most potent of the triptan series of drugs.^{[3][10][11][4]} It is also notable and unique among most of the triptans in being a potent serotonin 5-HT_2A receptor agonist (EC₅₀Tooltip half-maximal effective concentration = 7.9 nM), albeit with about one or two orders of magnitude lower activational potency than at the serotonin 5-HT_1B and 5-HT_1D receptors.^[6]

Chemistry

Donitriptan is a tryptamine derivative, a 5-substituted derivative of tryptamine and 5-methoxytryptamine, and an analogue of the psychedelic drugs dimethyltryptamine (DMT) and 5-MeO-DMT.^[12]

The predicted log P of donitriptan is 1.32 to 2.2.^[12][13]

History

Donitriptan was being developed in France by bioMérieux-Pierre Fabre and made it to phase II clinical trials in Europe before development was discontinued.^{[14][15][16][3]}

See also

• Triptan
• Avitriptan