Comparison of the cromakalim antagonism and bradycardic actions of a series of novel alinidine analogues in the rat.
Alinidine, and eight derivatives, were synthesized and tested for their ability to antagonise the actions of the K+ channel opener cromakalim in rat thoracic aorta, and for their ability to induce bradycardia in rat isolated spontaneously beating right atria. Ring segments of rat thoracic aorta were suspended in organ baths to record isometric tension. Tissues were precontracted with K+ (20 mM), and full concentration-relaxation curves constructed to cromakalim (0.01-30 microM) in the absence and presence of increasing concentrations of alinidine/derivative. The majority of the compounds tested caused rightward shifts in the cromakalim concentration-effect curves. Rat spontaneously beating right atria were suspended in organ baths to record rate of contraction. Addition of alinidine/derivative caused a concentration-dependent negative chronotropic response. In terms of structure-activity relationships, increasing the length of the N-allyl side-chain on the alinidine molecule (from 3 carbon (3C), to 5C) resulted in a significant increase in the activity of the compounds as both bradycardic agents and cromakalim antagonists. The most potent compounds in both cases (bradycardic agent and cromakalim antagonist) had no double bond in the side chain. The results suggest that the carbon side-chain influences the activity of alinidine-related compounds both as cromakalim antagonists and as bradycardic agents. However, while similar structure-activity relationships appear to apply for both effects in some instances, there was no significant correlation between the two actions of the alinidine analogues. The results suggest that the ability of alinidine-derivatives to induce bradycardia or to block K+ channels opened by cromakalim can be differentiated on the basis of structure.
Challinor-Rogers
J L
JL
Baker Medical Research Institute, Prahran, Australia.
Hay
T K
TK
McPherson
G A
GA
D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019806:Cromakalim; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D002317:Cardiovascular Agents; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; C022192:alinidine; D003000:Clonidine