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

• Published in: European journal of pharmacology Vol. 368; no. 2-3; pp. 259 - 268
• Main Authors: NAPIER, C, STEWART, M, MELROSE, H, HOPKINS, B, MCHARG, A, WALLIS, R
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 05.03.1999
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Cardiovascular system; Cell Line; Cold Temperature; COS Cells; HeLa Cells; Humans; Indoles - metabolism; Kinetics; Medical sciences; Oxazoles - metabolism; Oxazolidinones; Pharmacology. Drug treatments; Piperidines - metabolism; Pyrrolidines - metabolism; Radioligand Assay; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin - metabolism; Sumatriptan - metabolism; Triazoles - metabolism; Tritium; Tryptamines; Vasodilator agents. Cerebral vasodilators; Human; Agonist; Biological fixation; Recombination; Antimigrainous agent; Eletriptan; Affinity; 5-HT1 Serotonine receptor; In vitro; Comparative study
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(99)00026-6

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.