COMPARISON OF THE CROMAKALIM ANTAGONISM AND BRADYCARDIAC ACTIONS OF ASERIES OF NOVEL ALINIDINE ANALOGS IN THE RAT

Alinidine, and eight derivatives, were synthesized and tested for thei r ability to antagonise the actions of the K+ channel opener cromakali m in rat thoracic aorta, and for their ability to induce bradycardia i n rat isolated spontaneously beating right atria. Ring segments of rat thoracic aorta were suspended in organ baths to record isometric tens ion. Tissues were precontracted with K+ (20 mM), and full concentratio n-relaxation curves constructed to cromakalim (0.01-30 mu M) in the ab sence and presence of increasing concentrations of alinidine/derivativ e. The majority of the compounds tested caused rightward shifts in the cromakalim concentration-effect curves. Rat spontaneously beating rig ht atria were suspended in organ baths to record rate of contraction. Addition of alinidine/derivative caused a concentration-dependent nega tive chronotropic response. In terms of structure-activity relationshi ps, increasing the length of the N-allyl side-chain on the alinidine m olecule (from 3 carbon (3 C), to 5 C) resulted in a significant increa se in the activity of the compounds as both bradycardic agents and cro makalim antagonists. The most potent compounds in both cases (bradycar dic agent and cromakalim antagonist) had no double bond in the side ch ain. The results suggest that the carbon side-chain influences the act ivity of alinidine-related compounds both as cromakalim antagonists an d as bradycardic agents. However, while similar structure-activity rel ationships appear to apply for both effects some instances, there was no sig nificant correlation between the two actions of the alinidine a nalogues. The results suggest that the ability of alinidine-derivative s to induce bradycardia or to block K+ channels opened by cromakalim c an be differentiated on the basis of structure.