Characterisation of the 5-HT receptor binding profile of eletriptan and kinetics of [formula omitted]eletriptan binding at human 5-HT 1B and 5-HT 1D receptors

Abstract

The affinity of eletriptan (( R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl)ethyl]-1 H-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 [ 3 H] eletriptan and [ 3 H] 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, [ 3 H] eletriptan had over 6-fold higher affinity than [ 3 H] sumatriptan at the 5-HT 1D receptor ( K D: 0.92 and 6.58 nM, respectively) and over 3-fold higher affinity than [ 3 H] 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, [ 3 H] eletriptan had a significantly ( P<0.05) faster association rate ( K on 0.249 min −1 nM −1) than [ 3 H] 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 [ 3 H] 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.