Inhibition of the trigemino-vascular system with 5-HT1D agonist drugs: selectively targeting additional sites of action.
Inappropriate activation of the trigemino-vascular system is thought to be important in the pathogenesis of a migraine attack. The 5-HT1D agonist sumatriptan, which is highly effective in the acute treatment of migraine, inhibits trigemino-vascular activation in animals, although its actions are normally limited to peripheral components of the trigemino-vascular system. 311C90, a novel 5-HT1D agonist drug, which is also highly effective in the acute treatment of migraine, acts not only at these sites, but, additionally within the brainstem, inhibiting trigemino-vascular activation centrally as well as peripherally. This article describes the pre-clinical development of 311C90 and considers, specifically, the approaches taken in the design of a molecule with attributes which facilitate access to brainstem components of the trigeminal pathway and combine this with good oral bioavailability.
Martin
G R
GR
Wellcome Foundation, Beckenham, Kent, UK.
D000284:Administration, Oral; D001682:Biological Availability; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy*; D010080:Oxazoles / Q000627:therapeutic use; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014276:Trigeminal Nerve / Q000187:drug effects*; D014363:Tryptamines
D010080:Oxazoles; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan