THE PREJUNCTIONAL AND POSTJUNCTIONAL ACTIVITY OF CP-122,288, A CONFORMATIONALLY RESTRICTED ANALOG OF SUMATRIPTAN

The present study investigated the pre- and postjunctional activity of CP-122,288 (5-methyl-aminosulphonylmethyl-3-(N-methylpynolidin-2R-yl-methyl)-1H-indole), an analogue of the vascular 5-HT1 receptor agonist, sumatriptan. CP-122,288 inhibited neurogenic plasma protein extravasation in rat dura with a potency approximately 40000-fold greater than sumatriptan (ID50 values of 0.3 pmol/kg and 13.9 nmol/kg i.v. respectively). However, CP-122,288 was only approximately 2-fold more potent than sumatriptan at inhibiting neurogenically mediated contractions of the dog saphenous vein. CP-122,288 contracted the dog saphenous vein and basilar artery with a potency approximately 2-fold greater than that of sumatriptan. Both compounds possessed similar affinities at either human 5-HT1D alpha or 5-HT1D beta receptors. It is concluded that CP-122,288 exhibits a or 5-HT prejunctional selectivity in the meninges to inhibit dural plasma protein extravasation independent of 5-HT1D alpha and 5-HT1D beta receptor activation.