Effects of derivatives of NGP 1-01, a putative calcium channel antagonist, on electrically stimulated guinea-pig papillary muscle.
In earlier work we have reported calcium antagonistic properties for the polycyclic compound NGP 1-01. We now have derivatized NGP 1-01 by side-chain substitution to obtain ten novel aromatic and aliphatic imino-keto and amino-ether compounds. Electrophysiological tests were conducted on these compounds using isolated guinea-pig papillary muscle preparations to record calcium-mediated (slow) action potentials (APs). The lipophilicities of the compounds, expressed as chromatographically determined RM values, were measured and the molecular surface areas calculated. Several derivatives showed increased activity compared with NGP 1-01. All compounds with aromatic side-chains (benzyl, phenethyl, phenylpropyl) were active (concentrations required for complete suppression of the AP varied between 1 x 10(-5) M and 5 x 10(-5) M) and compounds with shorter (methyl, butyl) aliphatic side-chains were inactive whilst activity increased dramatically in those compounds with octyl side-chains. Lipophilicity and calculated molecular volumes correlated linearly and bulkier, more lipophilic molecules had increasing activities in the electrophysiological assay. We therefore conclude that bulky substituents on the nitrogen atom increase calcium antagonistic activity in this series of compounds.
Liebenberg
W
W
Potchefstroom University for CHE, Potchefstroom, South Africa.
Van der Walt
J J
JJ
Van der Schyf
C J
CJ
D000818:Animals; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D010210:Papillary Muscles / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship
D001952:Bridged-Ring Compounds; D002121:Calcium Channel Blockers; C049649:NGP 1-01