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 hyl-3-(N-methylpynolidin-2R-yl-methyl)-1H-indole), an anal ogue of the vascular 5-HT1 receptor agonist, sumatriptan. CP-122,288 i nhibited neurogenic plasma protein extravasation in rat dura with a po tency approximately 40000-fold greater than sumatriptan (ID50 values o f 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 inhibit ing neurogenically mediated contractions of the dog saphenous vein. CP -122,288 contracted the dog saphenous vein and basilar artery with a p otency approximately 2-fold greater than that of sumatriptan. Both com pounds 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-H T prejunctional selectivity in the meninges to inhibit dural plasma pr otein extravasation independent of 5-HT1D alpha and 5-HT1D beta recept or activation.