Comparison of the cromakalim antagonism and bradycardic actions of a series of novel alinidine analogues in the rat

Abstract

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.

HCN Channels Modulators: The Need for Selectivity

“…Opening the nitrogen-containing ring, or increasing its size, was detrimental for activity. An alkyl group (R 4 ) only on the endocyclic guanidine nitrogen atoms (R 3 = H), gave inactive compounds; however, derivative TH92:20 was four times more potent that alinidine in lowering heart rate [112]. Results of in vivo experiments are a combination of pharmacokinetic and pharmacodynamic properties, which makes difficult to derive sound structure-activity relationships; for this reason, physicochemical properties (pKa and logD 7.4 ) were also taken into account [112].…”

“…An alkyl group (R 4 ) only on the endocyclic guanidine nitrogen atoms (R 3 = H), gave inactive compounds; however, derivative TH92:20 was four times more potent that alinidine in lowering heart rate [112]. Results of in vivo experiments are a combination of pharmacokinetic and pharmacodynamic properties, which makes difficult to derive sound structure-activity relationships; for this reason, physicochemical properties (pKa and logD 7.4 ) were also taken into account [112]. The development of alinidine (ST-567) was stopped due to the many side effects of the compound, which were ascribed to the interaction with L-type Ca 2+ channels and K + channels, and to the metabolic transformation leading to clonidine [110, 113].…”

Functional and electrophysiological effects of a novel imidazoline‐based KATP channel blocker, IMID‐4F

“…alinidine and phentolamine) based compounds were antagonists of the vascular smooth muscle relaxant actions of cromakalim (McPherson & Angus, 1989; 1990). Using identical techniques as those used in the present experiments, the apparent pK B for alinidine in rat thoracic aorta was calculated at approximately 5.5 (Challinor‐Rogers et al ., 1994). The calculated pK B for IMID‐4F was calculated to be 7.10 which represents an overall increase in potency of 40 fold over that displayed by alinidine.…”

“…Apart from the sulphonylureas, a number of chemically unrelated groups of compounds have also been shown to antagonize the smooth muscle relaxant actions of K ATP channel openers in vascular and non‐vascular smooth muscle (Challinor‐Rogers & McPherson, 1994). In 1989 we showed that imidazolines such as alinidine, and chemically related compounds including phentolamine, were able to antagonize the functional and electrophysiological actions of K ATP channel openers, including levcromakalim, in vascular and non‐vascular smooth muscle (McPherson & Angus 1989; 1990; Challinor‐Rogers et al ., 1994; see Challinor‐Rogers & McPherson, 1994). Subsequent studies have shown that phentolamine and other imidazolines also inhibit K ATP channels in the pancreatic β‐cell (Dunne et al ., 1995), although the pA 2 or pK B values calculated for these imidazoline compounds have shown them to be some 30–100 times less potent than glibenclamide itself.…”