Target Validation Information
TTD ID T11072
Target Name 5-HT 1D receptor (HTR1D)
Type of Target
Successful
Drug Potency against Target Drug Info IC50 = 2.6 nM [20]
Eletriptan Drug Info Ki = 0.92 nM [21]
Frovatriptan Drug Info Ki = 3.98 nM [21]
Zolmitriptan Drug Info pKi = 8.88
Drug Info Ki = 20 nM [13]
Drug Info Ki = 265 nM [14]
Drug Info Ki = 3594 nM [8]
Drug Info Ki = 135 nM [14]
Drug Info Ki = 25 nM [12]
Drug Info Ki = 29 nM [12]
Drug Info Ki = 446 nM [8]
Drug Info IC50 = 0.6 nM [1]
Drug Info IC50 = 26 nM [16]
(+/-)-nantenine Drug Info Ki = 49 nM [10]
(3-Chloro-phenyl)-piperazin-1-yl-methanone Drug Info Ki = 17100 nM [13]
1,2,3,4-Tetrahydro-naphthalen-2-ylamine Drug Info Ki = 380 nM [14]
1-((S)-2-aminopropyl)-1H-indazol-6-ol Drug Info Ki = 7870 nM [7]
1-(2,5-Dimethoxy-4-methyl-phenyl)-piperazine Drug Info Ki = 680 nM [13]
1-(2,5-Dimethoxy-phenyl)-piperazine Drug Info Ki = 1035 nM [13]
1-(2,5-dimethoxyphenyl)propan-2-amine Drug Info Ki = 1020 nM [15]
1-(2-Butoxy-phenyl)-piperazine Drug Info Ki = 19.3 nM [12]
1-(2-Ethoxy-phenyl)-piperazine Drug Info Ki = 42.6 nM [12]
1-(2-Fluoro-phenyl)-piperazine Drug Info Ki = 57.9 nM [12]
1-(2-Isopropoxy-phenyl)-piperazine Drug Info Ki = 19 nM [12]
1-(3-Fluoro-phenyl)-piperazine Drug Info Ki = 86.5 nM [12]
1-(3-Nitro-phenyl)-piperazine Drug Info Ki = 250 nM [12]
1-(4-Bromo-2,5-dimethoxy-phenyl)-piperazine Drug Info Ki = 820 nM [13]
1-(7-Methoxy-naphthalen-2-yl)-piperazine Drug Info Ki = 0.7 nM [19]
1-naphthylpiperazine Drug Info Ki = 5 nM [14]
2-(2,6-Dimethyl-benzyl)-4,5-dihydro-1H-imidazole Drug Info Ki = 2210 nM [4]
2-(2-Amino-propyl)-5-bromo-4-methoxy-phenol Drug Info Ki = 1710 nM [15]
2-(2-Methoxy-phenyl)-1-methyl-ethylamine Drug Info Ki = 3500 nM [15]
2-(3-Methoxy-phenyl)-1-methyl-ethylamine Drug Info Ki = 2660 nM [15]
2-(4-Bromo-2-methoxy-phenyl)-1-methyl-ethylamine Drug Info Ki = 2900 nM [15]
2-(4-Bromo-phenyl)-1-methyl-ethylamine Drug Info Ki = 2830 nM [15]
2-(4-tert-Butyl-phenyl)-4,5-dihydro-1H-imidazole Drug Info Ki = 105 nM [4]
2-(5-Nonyloxy-1H-indol-3-yl)-ethylamine Drug Info Ki = 16 nM [17]
2-(5-Thiophen-2-yl-1H-indol-3-yl)-ethylamine Drug Info Ki = 1.7 nM [2]
2-Piperazin-1-yl-benzonitrile Drug Info Ki = 26.1 nM [12]
2-Piperazin-1-yl-phenol Drug Info Ki = 150 nM [13]
3-Amino-1-(2-amino-5-methoxy-phenyl)-propan-1-one Drug Info Ki = 345 nM [13]
5,6-dichloro-3,4-dihydroquinazolin-2-amine Drug Info Ki = 1265 nM [8]
5-amino-3-(N-methylpiperidin-4-yl)-1H-indole Drug Info Ki = 39.6 nM [9]
5-chloro-4-methyl-3,4-dihydroquinazolin-2-amine Drug Info Ki = 1272 nM [8]
5-Ethyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indole Drug Info Ki = 45 nM [3]
5-Isopropyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indole Drug Info Ki = 5.3 nM [3]
8-Methoxy-2-(4-methyl-piperazin-1-yl)-quinoline Drug Info Ki = 1900 nM [14]
8-Methoxy-2-piperazin-1-yl-quinoline Drug Info Ki = 415 nM [14]
8-Methoxy-quinolin-2-ylamine Drug Info Ki = 10400 nM [14]
AGROCLAVINE Drug Info IC50 = 140 nM [11]
Brolamfetamine Drug Info Ki = 3340 nM [15]
GR-127935 Drug Info Ki = 0.7 nM [6]
L-741604 Drug Info IC50 = 0.3 nM [1]
L-747201 Drug Info IC50 = 3.4 nM [18]
L-775606 Drug Info IC50 = 0.6 nM [9]
LY-334370 Drug Info Ki = 137 nM [9]
QUIPAZINE Drug Info Ki = 230 nM [14]
SEROTONIN Drug Info Ki = 0.5 nM [9]
WAY-466 Drug Info Ki = 65 nM [5]
[2-(5-Ethyl-1H-indol-3-yl)-ethyl]-dimethyl-amine Drug Info Ki = 16 nM [3]
Action against Disease Model Eletriptan Drug Info The functional activity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]- 1 H-indole) at the contractile serotonin (5-hydroxytryptamine; 5-HT) '1B-like' receptor in dog isolated saphenous vein and basilar artery was investigated. Eletriptan, like 5-HT and s uMatriptan potently contracted saphenous vein (pEC50: 6.3, 6.9 and 6.1, respectively)and basilar artery (pEC50 7.2, 7.5 and 6.8, respectively). The maxim uM responses evoked by eletriptan was, unlike s uMatriptan, significantly lower than that to 5-HT (intrinsic activity saphenous vein: eletriptan 0.57, 5-HT 1.0, s uMatriptan 0.85; basilar artery: eletriptan 0.77, 5-HT 0.98, s uMatriptan 0.89). Contractions evoked by eletriptan were antagonised by the 5-HT1B/1D receptor antagonist GR125743 (N-[4-methoxy-3-(4-methyl piperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide) with pA2 values of 9.1 in saphenous vein and 9.4 in basilar artery. Affinity estimates (pKA) for 5-HT and suMatriptan determined from receptor alkylation studies in saphenous vein were 6.6 and 6.3, respectively, compared to the apparent equilibri uM dissociation constant (pKp) for eletriptan of 6.8. The rank order of relative intrinsic efficacies (epsilon) was 5-HT > s uMatriptan > eletriptan. Thus, eletriptan required greater receptor occupancy (4.4-fold) to evoke an equivalent contraction to 5-HT and s uMatriptan in dog isolated saphenous vein. These data demonstrate that eletriptan is a potent partial agonist at the canine vascular 5-HT1B receptor.pEC50 on saphenous vein: 6.3 [22]
Frovatriptan Drug Info The contractile actions of the novel high-affinity 5-hydroxytryptamine (5-HT(1B/1D)) ligand, frovatriptan (formerly VML 251/SB-209509) were investigated in h uMan isolated basilar and coronary arteries in which the endotheli uM had been removed. Basilar arteries were obtained post mortem, and coronary arteries were obtained from patients undergoing heart transplant (recipient) or from donor hearts that were not suitable for transplant. Frovatriptan was a potent contractile agent in isolated basilar artery with a -log mean effective concentration (EC50) value of 7.86 +/- 0.07 and intrinsic activity of 1.25 +/- 0.10 relative to 5-HT (n = 4). Frovatriptan was 8.5-fold more potent than s uMatriptan, which produced a -log EC50 value of 6.93 +/- 0.09 and intrinsic activity11.1 +/- 0.08 relative to 5-HT (n = 4). In coronary arteries, frovatriptan produced contraction with -log EC50 values of 7.38 +/- 0.12 and 7.81 +/- 0.2 in recipient (n = 7) and donor (n = 3) arteries, respectively. The relative degree of contraction of frovatriptan was lower than that of 5-HT, with relative intrinsic activities of 0.42 +/- 0.06 and 0.40 +/- 0.09, respectively. S uMatriptan produced contraction of h uMan recipient and donor arteries with -log EC50 values (intrinsic activity) of 6.57 +/- 0.13 (0.79 +/- 0.27; n = 6) and 7.35 (1.41; n = 2), respectively. Furthermore, marked bell-shaped responses were apparent for frovatriptan in coronary arteries, with relaxation occurring at concentrations >6 microM in some tissues. In contrast, no bell-shaped concentration-response curves were apparent for s uMatriptan or 5-HT. Threshold concentrations for frovatriptan-induced contractions were also different between basilar (>2 nM) and coronary arteries (>20 nM). No separation of threshold activity was observed with s uMatriptan or 5-HT. These data show that frovatriptan produces constriction of h uMan isolated basilar and coronary arteries. However, frovatriptan produces a complexpharmacologic response in the coronary artery, with threshold contractile activity requiring approximately 10-fold greater concentrations of agonist than in the basilar artery. Frovatriptan also shows a differential pharmacologic profile compared with s uMatriptan in coronary arteries, with reversal of tone predominating at high concentration.-logEC50 on isolated basilar artery: 7.86 [24]
Rizatriptan Drug Info EC50 on vasoconstriction in isolated h uMan cranial arteries: 90nM [23]
References
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REF 16 Resolution and absolute configuration of the potent dopamine agonist N,N-diethyl-N'-[(3 alpha, 4a alpha, 10a beta)-1,2,3,4,4a,5,10,10a- -octahydro-... J Med Chem. 1985 Oct;28(10):1540-2.
REF 17 5-(Nonyloxy)tryptamine: a novel high-affinity 5-HT1D beta serotonin receptor agonist. J Med Chem. 1994 Sep 2;37(18):2828-30.
REF 18 Selective, orally active 5-HT1D receptor agonists as potential antimigraine agents. J Med Chem. 1997 Oct 24;40(22):3501-3.
REF 19 5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine. J Med Chem. 1997 Nov 21;40(24):3974-8.
REF 20 Agonistic properties of alniditan, sumatriptan and dihydroergotamine on human 5-HT1B and 5-HT1D receptors expressed in various mammalian cell lines. Br J Pharmacol. 1998 Apr;123(8):1655-65.
REF 21 Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
REF 22 Characterisation of the contractile activity of eletriptan at the canine vascular 5-HT1B receptor. Eur J Pharmacol. 1999 Feb 19;367(2-3):283-90.
REF 23 Rizatriptan in the treatment of migraine. Neuropsychiatr Dis Treat. 2006 Sep;2(3):247-59.
REF 24 Effects of the novel high-affinity 5-HT(1B/1D)-receptor ligand frovatriptan in human isolated basilar and coronary arteries. J Cardiovasc Pharmacol. 1998 Aug;32(2):220-4.

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