Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638 exhibit enhanced potency against neurogenic inflammation in dura mater

  title={Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638 exhibit enhanced potency against neurogenic inflammation in dura mater},
  author={Won S. Lee and Michael A. Moskowitz},
  journal={Brain Research},
CP-122,288 and CP-122,638 blocked plasma protein extravasation response within dura mater following trigeminal ganglion stimulation. The threshold (1 and 0.1 pmol/kg, respectively) was remarkably lower than for sumatriptan (7 nmol/kg), as was the dose at maximum response. As with sumatriptan, substance P-induced plasma leakage was unaffected by either compound, and metergoline only partially (27%) reversed the effects of CP-122,288. The data suggest the importance of modifications at the… 
The pre- and postjunctional activity of CP-122,288, a conformationally restricted analogue of sumatriptan.
It is concluded that CP-122,288 exhibits a prejunctional selectivity in the meninges to inhibit dural plasma protein extravasation independent of 5- HT1D alpha and 5-HT1D beta receptor activation.
Suppression by the sumatriptan analogue, CP‐122,288 of c‐fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin
Modifications at the amino‐ethyl side chain of sumatriptan dramatically enhance the suppression of c‐fos expression within TNC, a finding consistent with its remarkable potency against neurogenic plasma protein extravasation within dura mater.
The in vivo pharmacological profile of a 5‐HT1 receptor agonist, CP‐122, 288, a selective inhibitor of neurogenic inflammation
It is demonstrated that in the rat, CP‐122, 288 is a highly potent and selective inhibitor of neurogenic inflammation in intracranial tissues, at doses which are devoid of vasoconstrictor activity in dog and in the anaesthetized dog.
The 5-HT1D Receptor Antagonist GR-127,935 Prevents Inhibitory Effects of Sumatriptan but not CP-122,288 and 5-CT on Neurogenic Plasma Extravasation within Guinea Pig Dura Mater
The results suggest that 5-CT, as well as sumatriptan, act at a receptor linked to an inhibitory G-protein, which inhibits neurogenic inflammation via 5-HT1D alpha receptors in guinea pigs and 5- HT1D beta (5-HT 1B) receptors in rats.
Differential effects of low dose CP122,288 and eletriptan on Fos expression due to stimulation of the superior sagittal sinus in cat☆
The data suggest that activation of the 5HT(1B/1D) receptor is important for the clinical action of this class of compounds and is consistent with the fact the CP122,288 is ineffective in the treatment of the acute attack of migraine.
Effect of a 5‐HT1 receptor agonist, CP‐122,288, on oedema formation induced by stimulation of the rat saphenous nerve
The results suggest that CP‐122,288 is a potent inhibitor of neurogenic inflammation in rat skin and that the effect may be due to a prejunctional inhibition of neuropeptide release.
4991W93 inhibits release of calcitonin gene-related peptide in the cat but only at doses with 5HT1B/1D receptor agonist activity?
Given that 4991W93 is inactive clinically at non-vascular doses, it seems clear that the 5HT(1B/1D) agonist effects of the compound are necessary for blockade of CGRP release and thus any anti-migraine action.
Effects of PNU-109,291, a selective 5-HT1D receptor agonist, on electrically induced dural plasma extravasation and capsaicin-evoked c-fos immunoreactivity within trigeminal nucleus caudalis
Data indicate that the 5-HT1D receptor subtype plays a significant role in suppressing meningeal neurogenic inflammation and attenuating trigeminal nociception in these guinea pig models, and may become a useful therapeutic target for migraine and related headaches.
Neuroprotective effect of sumatriptan, a 5-HT(1D) receptor agonist, in focal cerebral ischemia of rat brain.
  • G. Mies
  • Medicine
    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
  • 1998
The reduction in the volume of ischemic injury in sumatriptan-treated animals is explained by both the improvement of blood flow and the inhibition of SD-like shifts leading to an amelioration of the misrelationship between the depolarization-related energy demand and flow-dependent substrate delivery.
4991W93, a potent blocker of neurogenic plasma protein extravasation, inhibits trigeminal neurons at 5-hydroxytryptamine (5-HT1B/1D) agonist doses
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.


Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine.
  • M. Moskowitz
  • Chemistry, Medicine
    Trends in pharmacological sciences
  • 1992
It is argued that blockade of neural transmission and the neurogenic inflammatory response provides a mechanism by which sumatriptan and ergot alkaloids alleviate vascular headaches.
Ergot alkaloids block neurogenic extravasation in dura mater: Proposed action in vascular headaches
It is proposed that the therapeutic effects of ergots in vascular headaches may result from peripheral blockade of small fiber (C or A‐delta)‐dependent neurogenic inflammation within the dura mater.
The synthesis of a conformationally restricted analog of the anti-migraine drug sumatriptan
The synthesis of 5-N-Methylaminosulfonylmethyl-3-(N-methylpyrrolidin-2-ylmethyl)indole (1), a conformationally restricted analog of the anti-migraine drug, sumatriptan, is described. To incorporate
Further characterization of the putative 5‐HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater
The above pharmacological data suggest that intracranial vessels possess 5‐HT receptor(s) which are coupled to inhibition of neurogenically‐mediated plasma protein extravasation.
CP‐93,129, a potent and selective 5‐HT1B receptor agonist blocks neurogenic plasma extravasation within rat but not guinea‐pig dura mater
Pretreatment with CP‐93,129 blocked plasma extravasation in rat dura mater induced by electrical trigeminal ganglion stimulation when administered at ≥140 nmol kg−1, i.v. but did not affect plasma
Role of 5‐HT1‐like receptors in the reduction of porcine cranial arteriovenous anastomotic shunting by sumatriptan
The selective reduction in arteriovenous anastomotic blood flow produced by sumatriptan may reflect its antimigraine action, thought to involve vasoconstriction of those cranial vessels, be they ‘shunt’ vessels or not, which are distended and inflamed during a migraine attack.
Treatment of migraine attacks with sumatriptan. The Subcutaneous Sumatriptan International Study Group.
  • L. Milne
  • Medicine
    The New England journal of medicine
  • 1991
It is concluded that a single 6-mg dose of sumatriptan given subcutaneously is a highly effective, rapid-acting, and well-tolerated treatment for migrane attacks.
Mode of action of the anti-migraine drug sumatriptan.