Serotonergic effects and extracellular brain levels of eletriptan, zolmitriptan and sumatriptan in rat brain

In vivo microdialysis was used to assess the central serotonergic effects and extracellular brain levels of the 5-HT1B/1D receptor agonists eletriptan, zolmitriptan and sumatriptan in rats after intravenous and intracerebral administration, while their binding affinities and functional potencies were determined at 5-HT1B, 5-HT1D and 5-HT1A receptors. In vitro studies showed that all three triptans are high affinity, full agonists at 5-HT1B/1D receptors, but that sumatriptan is functionally less potent as a 5-HT1B/1D agonist than zolmitriptan and eletriptan. Local intracortical perfusion with the compounds via the dialysis probe decreased cortical 5-HT (5-hydroxytryptamine, serotonin) release with ED50 values of approximately 0.1 muM for eletriptan and zolmitriptan and 0.5 muM for sumatriptan. At 3.2 mg/kg i.v., both eletriptan and zolmitriptan decreased 5-HT levels by about 35%, while sumatriptan had no effect, despite the fact that maximal sumatriptan concentrations in cortical dialysates were higher (8.8 nM at 20 min) than those of zolmitriptan (5.9 nM at 20 min) and eletriptan (2.6 nM at 40 min). The observation that eletriptan and zolmitriptan produce almost identical central serotonergic effects, after intracerebral as well as after systemic administration, is in agreement with their comparable functional 5-HT1B/1D receptor agonist potencies and their free levels in cortical dialysates after 3.2 mg/kg i.v. On the other hand, the lack of central serotonergic effects of 3.2 mg/kg i.v. sumatriptan is likely due to its weaker functional 5-HT1B/1D receptor agonist potency than eletriptan and zolmitriptan, rather than lower brain levels, consistent with sumatriptan's fivefold lower potency after intracerebral administration. (C) 2001 Elsevier Science B.V. All rights reserved.