title: Hydrophobic properties of novel dihydronaphthyridine calcium antagonists and biological activity in porcine isolated cardiac and vascular smooth muscle.
abstract: Dihydronaphthyridine calcium antagonists are structurally related to the well known dihydropyridines and act in a similar manner. In order to establish the vascular selectivity of these compounds contractile force was evaluated in porcine isolated ventricular trabeculae and right coronary arteries. The dihydropyridine derivatives nisoldipine and nitrendipine as well as the structurally different compounds gallopamil and flunarizine were included for comparison purpose. All compounds studied exhibited dose-dependent negative inotropic and vasodilator activities. The negative inotropic potency of all dihydronaphthyridines, especially of the highly lipophilic bulky ester-variated derivatives (Goe 5584-A, Goe 5806-A) was comparable to that of flunarizine but was considerably less pronounced than that of nisoldipine, nitrendipine or gallopamil. By contrast, half-maximal vasodilator responses of the dihydronaphthyridines studied in coronary arteries being in the nanomolar concentration range were comparable to the dihydropyridines nisoldipine and nitrendipine, whereas the activity of gallopamil and flunarizine was less marked. On the other side the dihydronaphthyridines, especially the more hydrophilic 3-ethylester-4-(2-cyanophenyl) derivative Goe 5606, exerted an obvious biphasic concentration-response behaviour in coronary arteries leading to a high affinity relaxant process in subnanomolar concentrations, whereas the low affinity response could be observed at rather high concentrations (mostly greater than 1 microM). Mainly due to their relative uneffectiveness in cardiac muscle, vascular selectivity of the dihydronaphthyridines was considerably higher than that of the structurally related dihydropyridines nisoldipine resp. nitrendipine increasing in the following order: nitrendipine less than nisoldipine less than Goe 5606 less than Goe 5438 less than Goe 5584-A less than Goe 5806-A. By contrast, gallopamil exerted a slight cardiac preference, whereas the vascular selectivity of flunarizine was also pronounced.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Institut für Pharmakologie, Universität zu Köln, Federal Republic of Germany.
authors.forename: G
authors.initials: G
authors.lastname: Werner
authors.forename: W
authors.initials: W
authors.lastname: Klaus
authors.forename: G
authors.initials: G
authors.lastname: Kojda
authors.forename: U
authors.initials: U
authors.lastname: Fricke
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003331:Coronary Vessels / Q000187:drug effects; D003864:Depression, Chemical; D005260:Female; D005711:Gallopamil / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D015737:Nisoldipine / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D009287:Naphthyridines; D014665:Vasodilator Agents; D005711:Gallopamil; D015737:Nisoldipine; D009568:Nitrendipine; D011188:Potassium