Ki-3005

1. KRN4884 (5-amino-N-[2-(2-chlorophenyl) ethyl]-N'-cyano-3-pyridinecarboxamidine), Ki3005 (5-deamino KRN4884), Ki5624 (2-dechloro KRN4884) and Ki1769 (5-deamino-2-dechloro KRN4884) produced concentration-dependent relaxations in isolated porcine coronary arteries contracted by 25 mM KC1. The order of relaxant potency was KRN4884 > Ki3005 > Ki5624 > Ki1769. 2. The relaxation induced by these compounds was antagonized by glibenclamide; they had almost no effect on coronary arteries contracted by 60 mM KC1. 3. The present results suggest that these pyridinecarboxamidine derivatives have vasodilating ability based on a K+ channel opening action, and that both the amino groups in the pyridine nucleus and the chlorine atom in the benzene nucleus in pyridinecarboxamidine are important for their potency as a K+ channel opener.

The potency and mechanism of the vasodepressor action of N-cyano-3-pyridinecarboximidamide and nicotinamide, which are 3-pyridine derivatives possessing cyanoamidine and amide structures, respectively, were studied in pithed rats infused with phenylephrine. The N-substituents of cyanoamidine and amide in the derivatives studied comprised 2-nitroxyethyl (KRN2391 and nicorandil), phenethyl (Ki769 and Ki765) and 2-(2-chlorophenyl)ethyl (Ki3005 and Ki4261) moieties. These derivatives produced vasodepressor actions in a dose-dependent manner, except for Ki4261 which did not show any action below the solubility limit. When the vasodepressor effects of compounds possessing the same N-substituents in cyanoamidine and amide derivatives were compared, the potency of cyanoamidine derivatives was greater than that of amide derivatives, Ki3005 being the most potent. The vasodepressor effects of cyanoamidine and amide derivatives were antagonized by glibenclamide, although the antagonism of the depressor effects of KRN2391 and nicorandil was less pronounced than that of the other derivatives. These results suggest that N-substituents, in addition to the cyanoamidine structure, play an important role in determining the vasodepressor potencies of 3-pyridine derivatives. Furthermore, the vasodepressor effects of these derivatives appear to be based on their K+ channel-opening actions, although those of KRN2391 and nicorandil seem to be partly mediated by a nitrate-like action in addition to their K+ channel-opening action.