title: 4991W93, a potent blocker of neurogenic plasma protein extravasation, inhibits trigeminal neurons at 5-hydroxytryptamine (5-HT1B/1D) agonist doses.
abstract: Triptans share the pharmacological profile of being 5-hydroxytryptamine (5-HT1B/1D) agonists and having potent anti-migraine activity. The conformationally restricted zolmitriptan analogue 4991W93 was developed as a potent, and at low doses, specific, non-vasconstrictor inhibitor of neurogenic dural plasma protein extravasation. Here, we sought to study the effect of 4991W93 at plasma protein extravasation blocking and at 5-HT(1B/1D) agonist doses. Nociceptive cells with firing latencies consistent with Adelta fibres were recorded in the dorsal horn region of the trigeminal nucleus caudalis after electrical stimulation of the sagittal sinus. Both evoked (13 units) and free running (6 units) activity in cells linked to sagittal sinus stimulation were inhibited by 4991W93 delivered microiontophoretically or by intravenous administration at 10 microg/kg or 100 microg/kg, but not 0.1 microg/kg. When applied iontophoretically, 4991W93 did not appear to have an additive effect over a 5-HT(1B/1D) agonist effective concentration of zolmitriptan. These data suggest that 4991W93 is only effective at modulating the trigeminocervical complex at 5-HT(1B/1D) agonist doses. To account for neurogenic dural plasma protein extravasation blockade in animal studies, 4991W93 might have non-5-HT(1B/1D)-based pharmacological targets that are yet to be described.
authors.affiliation: Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, WC1N 3BG, London, UK
authors.forename: R J
authors.initials: RJ
authors.lastname: Storer
authors.forename: S
authors.initials: S
authors.lastname: Akerman
authors.forename: H E
authors.initials: HE
authors.lastname: Connor
authors.forename: P J
authors.initials: PJ
authors.lastname: Goadsby
mesh_terms: D000818:Animals; D002415:Cats; D007211:Indoles / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology*; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D014276:Trigeminal Nerve / Q000187:drug effects* / Q000502:physiology
chemical_list: C423339:4991W93; D007211:Indoles; D010080:Oxazoles; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists