Characterisation of the 5-HT receptor binding profile of eletriptan and kinetics of [³H]eletriptan binding at human 5-HT(1B) and 5-HT(1D) receptors

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-HT(1B/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-HT(1B), 5-HT(1D) and putative 5-ht(1f) receptor. Kinetic studies comparing the binding of [³H]eletriptan and [³H]sumatriptan to the human recombinant 5-HT(1B) and 5-HT(1D) 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-HT(1D) receptor (K(D): 0.92 and 6.58 nM, respectively) and over 3-fold higher affinity than [³H]sumatriptan at the 5-HT(1B) 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-HT(1D) receptor and then only at 4°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-HT(1B), 5-HT(1D) and 5-ht(1f) receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache. Copyright (C) 1999 Elsevier Science B.V.