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S D Kimball

Publications and source records attributed to S D Kimball.

23 records · Page 2Linked to original sources
PubMed1990

Dihydropyrimidine calcium channel blockers. 2. 3-substituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.

To enhance the intrinsic potency of dihydropyrimidine calcium channel blockers, we have modified the structure of previously described 2-heteroalkyl-1,4-dihydropyrimidines 2 to 3-substituted 1,4-dihydropyrimidines 3. Structure-activity studies using potassium-depolarized rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more potent than either ortho- or meta-monosubstituted compounds. While vasorelaxant activity was critically dependent on the size of the C5 ester group, isopropyl ester being the best, a variety of substituents (carbamate, acyl, sulfonyl, alkyl) were tolerated at N3. Our results show dihydropyrimidines 3 are significantly more potent than corresponding 2-heteroalkyl-1,4-dihydropyrimidines 2 and only slightly less potent than similarly substituted 2-heteroalkyl-1,4-dihydropyridines 4 and 5. Whereas dihydropyridine enantiomers usually show 10-15-fold difference in activity, the enantiomers of dihydropyrimidine 3j show more than a 1000-fold difference in activity. These results strengthen the requirement of an enamino ester for binding to the dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.

Animals↗
PubMed1988

Studies directed toward ascertaining the active conformation of 1,4-dihydropyridine calcium entry blockers.

A series of unsymmetrically substituted 4-phenyl-1,4-dihydropyridine calcium entry blockers were investigated for their ability to relax potassium-contracted rabbit aortic smooth muscle and to competitively displace [3H]nitrendipine from its specific binding sites on guinea pig myocardial membranes in order to delineate the pharmacologically active conformer with respect to the position of the aromatic substituent (synperiplanar or antiperiplanar). The data show that the 1,4-dihydropyridine receptor distinguishes between 2',3'-disubstituted phenyldihydropyridines and 2',5'-disubstituted analogues as measured by changes of vasodilation and receptor affinity in vitro. The IC50 values for vasorelaxation by the analogues presented here correlate best with the Kd values for binding to the predominant receptor of two coexisting dihydropyridine binding sites in the guinea pig myocardium. We report the first observation of an antiperiplanar orientation of an o-phenyl substituent in the X-ray structure of 2-chlorophenyl analogue 3. Using nuclear Overhauser enhancement, we have developed a method that also demonstrates that an ortho (chloro or nitro) substituent on the phenyl ring does not preclude the presence of either synperiplanar or antiperiplanar phenyl rotamer in solution. These experimental findings contrast with the accepted belief that o-phenyl substituents essentially force these 1,4-dihydropyridines into the synperiplanar conformation exclusively.

Animals↗
PubMed1988

Pressor responses induced by Bay K 8644 involve both release of adrenal catecholamines and calcium channel activation.

1. The dihydropyridine calcium channel activator, Bay K 8644, is believed to increase mean arterial blood pressure in several animal models, as a result of direct activation of vascular smooth muscle cells by increasing calcium influx through the voltage-dependent calcium channels. The purpose of the current study was to elucidate further the mechanism of action of Bay K 8644, by examining the possibility that the pressor response to Bay K 8644 may also be the result of indirect activation of the vascular smooth muscle cells by release of adrenal catecholamines. 2. Intravenous administration of Bay K 8644 increased mean arterial pressure in a dose-dependent manner in conscious, normotensive rats. This pressor response was blocked by calcium channel blockers (nifedipine, verapamil, and diltiazem) at doses lower than were necessary to decrease resting mean arterial pressure. 3. alpha-Adrenoceptor antagonists (phentolamine, yohimbine, and prazosin) completely blocked the Bay K 8644-induced pressor responses and converted them to depressor responses. Adrenalectomy did not alter the inhibitory effect of phentolamine on the pressor response to Bay K 8644. However, adrenalectomy or adrenal demedullectomy prevented the phentolamine-induced reversal of the Bay K 8644 pressor response to a depressor response. In addition, adrenalectomy did not affect the ability of phentolamine to reverse the pressor response to exogenous adrenaline administration to a depressor response. 4. These data suggest that the pressor response to Bay K 8644 may involve both direct activation of vascular smooth muscle cells and indirect activation of the muscle cells by release of adrenal catecholamines.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗