Effect of new and known 1,4-dihydropyridine derivatives on blood glucose levels in normal and streptozotocin-induced diabetic rats.
Analysis of the effect of several 1,4-DHP Ca(2+) channel antagonists on experimental and clinical diabetes shows that structurally similar Ca(2+) channel antagonists can exert opposite effects on Ca(2+) influx, glucose homeostasis and insulin secretion. The influence of the Ca(2+) channel antagonists on pancreatic beta cell functions is dependent on lipophilicity, interactions with the cell membrane lipid bilayer, with SNAREs protein complexes in cell and vesicle membranes, with intracellular receptors, bioavailability and time of elimination from several organs and the bloodstream. In the present work we studied the effect at several doses of new compounds synthesized in the Latvian Institute of Organic Synthesis on blood glucose levels in normal and STZ-induced diabetic rats. The compounds tested were: 1,4-DHP derivatives cerebrocrast (1), etaftoron (2), OSI-1190 (3), OSI-3802 (4), OSI-2954 (5) and known 1,4-DHP derivatives: niludipine (6), nimodipine (7) and nicardipine (8) which possess different lipophilicities. Analysis of the structure-function relationships of the effect of 1,4-DHP derivatives on glucose metabolism showed that cerebrocrast could evoke qualitative differences in activity. Insertion of an OCHF(2) group in position 2 of the 4-phenylsubstituent and propoxyethylgroup R in ester moieties in positions 3 and 5 of the DHP structure, as well as an increase in the number of carbon atoms in the ester moiety, significantly modified the properties of the compound. Thereby cerebrocrast acquired high lipophilicity and membranotropic properties. Cerebrocrast, in a single administration at low doses (0.05 and 0.5 mg x kg(-1), p.o.), significantly decreased the plasma level of glucose in normal rats and in STZ-induced diabetic rats returned plasma glucose to basal levels. This effect was characterized by a slow onset and a powerful long-lasting influence on glucose metabolism, especially in STZ-induced diabetic rats.
Briede
Janīna
J
Latvian Institute of Organic Synthesis, Riga, Latvia.
Stivriņa
Māra
M
Stoldere
Dzintra
D
Bisenieks
Egīls
E
Uldriķis
Jānis
J
Poikāns
Jānis
J
Makarova
Natālija
N
Duburs
Gunārs
G
D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D050600:SNARE Proteins / Q000502:physiology; D013311:Streptozocin; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007004:Hypoglycemic Agents; C530983:OSI 3802; C541339:OSI-1190; C541340:OSI-2954; D050600:SNARE Proteins; C530982:etaftoron; C073838:2,6-dimethyl-3,5-bis(2'-propoxyethoxycarbonyl)-4-(2''-difluoromethoxyphenyl)-1,4-dihydropyridine; D013311:Streptozocin; C038806:1,4-dihydropyridine; C019497:niludipin; D009543:Nifedipine