Target Validation Information
Target ID T11072
Target Name 5-hydroxytryptamine 1D receptor
Target Type
Successful
Drug Potency against Target Eletriptan Drug Info Ki = 0.92 nM [537564]
Frovatriptan Drug Info Ki = 3.98 nM [537564]
GR-127935 Drug Info Ki = 0.7 nM [527726]
1-(3-Fluoro-phenyl)-piperazine Drug Info Ki = 86.5 nM [533134]
3-Amino-1-(2-amino-5-methoxy-phenyl)-propan-1-one Drug Info Ki = 345 nM [533476]
1-Naphthalen-2-yl-piperazine Drug Info Ki = 265 nM [533482]
1-(3-Nitro-phenyl)-piperazine Drug Info Ki = 250 nM [533134]
1-(2-Ethoxy-phenyl)-piperazine Drug Info Ki = 42.6 nM [533134]
2-(4-Bromo-phenyl)-1-methyl-ethylamine Drug Info Ki = 2830 nM [533498]
5-chloro-3,4-dihydroquinazolin-2-amine Drug Info Ki = 3594 nM [529148]
PHENYLPIPERAZINE Drug Info Ki = 135 nM [533482]
2-(5-Nonyloxy-1H-indol-3-yl)-ethylamine Drug Info Ki = 16 nM [533876]
2-(4-Bromo-2-methoxy-phenyl)-1-methyl-ethylamine Drug Info Ki = 2900 nM [533498]
(3-Chloro-phenyl)-piperazin-1-yl-methanone Drug Info Ki = 17100 nM [533476]
Brolamfetamine Drug Info Ki = 3340 nM [533498]
2-(4-tert-Butyl-phenyl)-4,5-dihydro-1H-imidazole Drug Info Ki = 105 nM [527180]
L-747201 Drug Info IC50 = 3.4 nM [534500]
1-(7-Methoxy-naphthalen-2-yl)-piperazine Drug Info Ki = 0.7 nM [534528]
QUIPAZINE Drug Info Ki = 230 nM [533482]
8-Methoxy-2-(4-methyl-piperazin-1-yl)-quinoline Drug Info Ki = 1900 nM [533482]
1-Naphthalen-1-yl-piperazine Drug Info Ki = 5 nM [533482]
2-(5-Thiophen-2-yl-1H-indol-3-yl)-ethylamine Drug Info Ki = 1.7 nM [525792]
5-amino-3-(N-methylpiperidin-4-yl)-1H-indole Drug Info Ki = 39.6 nM [529496]
1-(2-Butoxy-phenyl)-piperazine Drug Info Ki = 19.3 nM [533134]
L-775606 Drug Info IC50 = 0.6 nM [529496]
2-(2,6-Dimethyl-benzyl)-4,5-dihydro-1H-imidazole Drug Info Ki = 2210 nM [527180]
Zolmitriptan Drug Info pKi = 8.88
LY-334370 Drug Info Ki = 137 nM [529496]
5,6-dichloro-3,4-dihydroquinazolin-2-amine Drug Info Ki = 1265 nM [529148]
8-Methoxy-2-piperazin-1-yl-quinoline Drug Info Ki = 415 nM [533482]
1-(2-Fluoro-phenyl)-piperazine Drug Info Ki = 57.9 nM [533134]
1-(2-Isopropoxy-phenyl)-piperazine Drug Info Ki = 19 nM [533134]
CHLOROPHENYLPIPERAZINE Drug Info Ki = 25 nM [533134]
1-(2-Methoxy-phenyl)-piperazine Drug Info Ki = 29 nM [533134]
1-(4-Bromo-2,5-dimethoxy-phenyl)-piperazine Drug Info Ki = 820 nM [533476]
2-(3-Methoxy-phenyl)-1-methyl-ethylamine Drug Info Ki = 2660 nM [533498]
1-(2,5-Dimethoxy-phenyl)-piperazine Drug Info Ki = 1035 nM [533476]
8-methoxy-4-methyl-3,4-dihydroquinazolin-2-amine Drug Info Ki = 446 nM [529148]
1-(2,5-Dimethoxy-4-methyl-phenyl)-piperazine Drug Info Ki = 680 nM [533476]
2-(2-Methoxy-phenyl)-1-methyl-ethylamine Drug Info Ki = 3500 nM [533498]
SEROTONIN Drug Info Ki = 0.5 nM [529496]
5-chloro-4-methyl-3,4-dihydroquinazolin-2-amine Drug Info Ki = 1272 nM [529148]
[2-(5-Ethyl-1H-indol-3-yl)-ethyl]-dimethyl-amine Drug Info Ki = 16 nM [525845]
Sumatriptan Drug Info IC50 = 2.6 nM [534635]
(+/-)-nantenine Drug Info Ki = 49 nM [530558]
L-741604 Drug Info IC50 = 0.3 nM [525431]
L-760790 Drug Info IC50 = 0.6 nM [525431]
2-Piperazin-1-yl-benzonitrile Drug Info Ki = 26.1 nM [533134]
5-Isopropyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indole Drug Info Ki = 5.3 nM [525845]
WAY-466 Drug Info Ki = 65 nM [527381]
5-Ethyl-3-(2-pyrrolidin-1-yl-ethyl)-1H-indole Drug Info Ki = 45 nM [525845]
AGROCLAVINE Drug Info IC50 = 140 nM [532683]
1,2,3,4-Tetrahydro-naphthalen-2-ylamine Drug Info Ki = 380 nM [533482]
8-Methoxy-quinolin-2-ylamine Drug Info Ki = 10400 nM [533482]
2-Piperazin-1-yl-phenol Drug Info Ki = 150 nM [533476]
1-(3-Trifluoromethyl-phenyl)-piperazine Drug Info Ki = 20 nM [533476]
Etisulergine Drug Info IC50 = 26 nM [533501]
1-(2,5-dimethoxyphenyl)propan-2-amine Drug Info Ki = 1020 nM [533498]
2-(2-Amino-propyl)-5-bromo-4-methoxy-phenol Drug Info Ki = 1710 nM [533498]
1-((S)-2-aminopropyl)-1H-indazol-6-ol Drug Info Ki = 7870 nM [527952]
Action against Disease Model Frovatriptan 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 [553276] Drug Info
Rizatriptan EC50 on vasoconstriction in isolated h uMan cranial arteries: 90nM [552938] Drug Info
Eletriptan 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 [552178] Drug Info
References
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Ref 527180Bioorg Med Chem Lett. 2004 Sep 20;14(18):4697-9.2-(Anilino)imidazolines and 2-(benzyl)imidazoline derivatives as h5-HT1D serotonin receptor ligands.
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Ref 529148Bioorg Med Chem Lett. 2008 Jan 1;18(1):256-61. Epub 2007 Oct 30.Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: structure-activity relationship elucidation.
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Ref 533134J Med Chem. 1989 May;32(5):1052-6.Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.
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