title: Characterisation of the 5-HT receptor binding profile of eletriptan and kinetics of [3H]eletriptan binding at human 5-HT1B and 5-HT1D receptors.
abstract: The affinity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]-1H-indole) for a range of 5-HT receptors was compared to values obtained for other 5-HT1B/1D receptor agonists known to be effective in the treatment of migraine. Eletriptan, like sumatriptan, zolmitriptan, naratriptan and rizatriptan had highest affinity for the human 5-HT1B, 5-HT1D and putative 5-ht1f receptor. Kinetic studies comparing the binding of [3H]eletriptan and [3H]sumatriptan to the human recombinant 5-HT1B and 5-HT1D receptors expressed in HeLa cells revealed that both radioligands bound with high specificity (>90%) and reached equilibrium within 10-15 min. However, [3H]eletriptan had over 6-fold higher affinity than [3H]sumatriptan at the 5-HT1D receptor (K(D)): 0.92 and 6.58 nM, respectively) and over 3-fold higher affinity than [3H]sumatriptan at the 5-HT1B receptor (K(D): 3.14 and 11.07 nM, respectively). Association and dissociation rates for both radioligands could only be accurately determined at the 5-HT1D receptor and then only at 4 degrees C. At this temperature, [3H]eletriptan had a significantly (P<0.05) faster association rate (K(on) 0.249 min(-1) nM(-1)) than [3H]sumatriptan (K(on) 0.024 min(-1) nM(-1)) and a significantly (P<0.05) slower off-rate (K(off) 0.027 min(-1) compared to 0.037 min(-1) for [3H]sumatriptan). These data indicate that eletriptan is a potent ligand at the human 5-HT1B, 5-HT1D, and 5-ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache.
authors: Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent, UK.
authors: C
authors: C
authors: Napier
authors: M
authors: M
authors: Stewart
authors: H
authors: H
authors: Melrose
authors: B
authors: B
authors: Hopkins
authors: A
authors: A
authors: McHarg
authors: R
authors: R
authors: Wallis
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002460:Cell Line; D003080:Cold Temperature; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D007700:Kinetics; D010080:Oxazoles / Q000378:metabolism; D023303:Oxazolidinones; D010880:Piperidines / Q000378:metabolism; D011759:Pyrrolidines / Q000378:metabolism*; D011869:Radioligand Assay; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000378:metabolism*; D018170:Sumatriptan / Q000378:metabolism; D014230:Triazoles / Q000378:metabolism; D014316:Tritium; D014363:Tryptamines
chemical_list: C470302:HTR1B protein, human; D007211:Indoles; D010080:Oxazoles; D023303:Oxazolidinones; D010880:Piperidines; D011759:Pyrrolidines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D014230:Triazoles; D014363:Tryptamines; D014316:Tritium; C115647:eletriptan; C089750:zolmitriptan; C093622:rizatriptan; D018170:Sumatriptan; C106783:naratriptan