Characterisation of the 5-HT receptor binding profile of eletriptan and kinetics of [H-3]eletriptan binding at human 5-HT1B and 5-HT1D receptors

The affinity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phe nylsulphonyl)ethyl]-1H-indole) for a range of 5-HT receptors was compared t o values obtained for other 5-HT1B/1D receptor agonists known to be effecti ve 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-ht(1f) receptor. Kinetic studies comparing the binding of [H-3]eletriptan and [H-3]sumatriptan to the human recombinant 5-HT1B and 5-HT1D receptors expressed in HeLa cells revealed that both radioligands b ound with high specificity (> 90%) and reached equilibrium within 10-15 min . However, [H-3]eletriptan had over 6-fold higher affinity than [H-3]sumatr iptan at the 5-HT1D receptor(K-D: 0.92 and 6.58 nM, respectively) and over 3-fold higher affinity than [H-3]sumatriptan at the 5-HT1B receptor (K-D: 3 .14 and 11.07 nM, respectively). Association and dissociation rates for bot h radioligands could only be accurately determined at the 5-HT1D receptor a nd then only at 4 degrees C. At this temperature, [H-3]eletriptan had a sig nificantly (P < 0.05) faster association rate (K-on 0.249 min(-1) nM(-1)) t han [H-3]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 [H- 3]sumatriptan). These data indicate that eletriptan is a potent ligand at t he human 5-HT1B, 5-HT1D and 5-ht(1f) receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment o f migraine headache. (C) 1999 Elsevier Science B.V. All rights reserved.