A search for calcium-channel activators in the verapamil series

A new series of phenylalkylamines related to Verapamil have been synthesized and their Ca2+-modulating activity on rabbit aorta and on guinea-pig heart were evaluated. The compounds display only a moderate Ca2+-antagonistic activity; none of them showed any Ca2+-agonistic effect.     

Characterization, localization and pharmacological profile of a high-affinity [3H]lidocaine binding site

Electrophysiological findings support the existence of voltage-dependent, sodium channel-associated receptors for class I antiarrhythmics. We have tried to identify such receptors with tritiated lidocaine. High-affinity binding sites were discovered in heart and brain membranes, but liver and kidney particulate fractions had the highest density of sites. The dissociation constants were 75 nM in bovine heart and 29 nM in guinea-pig liver membranes. Binding was reversible (t 1/2: 102 s at 2 degrees C), optimal at pH 9-10 and was only partly destroyed by heat treatment. Subcellular fractionation experiments excluded a plasmalemmal association of the lidocaine site in heart. The competition profile of 16 antiarrhythmics indicated chemical comparability of the sites in heart and liver. These data greatly challenge the applicability of labeled lidocaine as sodium channel probe. The pharmacological significance of the site described here remains to be clarified.     

Relaxant activity in rat aorta and trachea, conversion to a muscarinic receptor antagonist and structure-activity relationships of new K(ATP) activating 6-varied benzopyrans.

To characterize ATP-sensitive channels (K(ATP) channels) benzopyrans with different substituents at position 6 were synthesized as new K(ATP)-activators. Their relaxant potencies were determined in rat aorta and trachea. In aorta, pEC50-values (-log, M) ranged from 7.37 to 5.43; in trachea, pEC50-values were 0.3 to 0.8 log units lower. Functional data were compared with binding data obtained in calf tracheal cells using the cyanoguanidine [3H]P1075 (N-cyano-N'-1,1-dimethyl[2,3(n)-3H]propyl)-N11-(3-pyridinyl)guanidine) as radioligand. A high correlation (r = 0.96) between pEC50- and pKD-values indicated that tracheal relaxation produced by benzopyrans is mediated via K(ATP) channels without signal amplification. The permanently charged trimethylammonium derivative designed as a probe for the membrane site of action completely lost its affinity for K(ATP) channels, but converted to an antagonist for muscarinic acetylcholine receptors (pK(B) = 6.12+/-0.10), as confirmed in radioligand binding studies (pK(D) = 5.77+/-0.04). Structure-activity analyses revealed that the 6-substituent influences biological activity by a direct receptor interaction of its own and not indirectly by withdrawing electrons from the benzopyran nucleus. The variance of the biological activity is primarily determined by electrostatic properties, but desolvation energies additionally contribute.     

Structure-activity relationships of K(ATP) channel openers

Given their many physiological functions, K(ATP) channels represent promising drug targets. Sulfonylureas like glibenclamide block K(ATP) channels; they are used in the therapy of type 2 diabetes. Openers of K(ATP) channels (KCOs) e.g. relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols. Structure-activity relationships of the main chemical classes of KCOs are discussed.     

Inhibition of calmodulin dependent c-AMP-phosphodiesterase by moxaverine and papaverine

Vasodilator properties of papaverine and moxaverine have been attributed to an inhibition of cyclic adenosine monophosphate (c-AMP) phosphodiesterase (PDE). The discovery of the calmodulin (CaM) dependence of c-AMP PDE activity necessitates a reinvestigation of the molecular mode of action of papaverine-like compounds. Separately analyzing the inhibition of basal and CaM-stimulated enzyme activity by these drugs proves the preferred inhibition of the CaM stimulated c-AMP PDE. Lipophilicity is assumed to represent an indicator of CaM-inhibitory potency.     

Analysis of the action of cardio-active drugs

The Cellular Localization of Heart-Active Drugs The effect of N-methyl quaternization on the negative inotropic potency of heart-active compounds has been investigated to elucidate the membraneous site of action. In addition, the cellular localization of the Ca antagonist verapamil has been measured by means of the LAMMA analysis.