EPC syntheses and structure-activity relationships of hypoglycaemic semicyclic amidines.
A series of homochiral sterically hindered mono- and bicyclic amidines was prepared as hypoglycaemic agents by lethargic reaction of O-methylcaprolactim and 3-ethoxy-2-azabicyclo[2.2.2]oct-2-ene, respectively, with homochiral cis-2-substituted cyclopentane amines provided by asymmetrical reductive amination of racemic 2-substituted cyclopentanones. All compounds, except the cyclohexylmethyl-isoquinuclidone derivative which inhibited secretion at 100 microM, significantly stimulated insulin secretion 2-8-fold at 10 microM and 100 microM in INS-1 cells. The most potent activator was the 2-cyclopentyl-substituted caprolactam derivative 5e. The stimulatory effects on secretion increased with rising steric hindrance of both the amidine alpha-carbon and the bicyclic amidine moiety itself. Enantiomeric discrimination was observed for the 2-¿(cis-2-bulkysubstituted cyclopentyl)iminohexahydroazepine halides 5e and 5f and for the 3-¿(cis-2-substituted cyclopentyl)imino-2-azabicyclo¿2.2.2ŏctane halides 6a and 6c. The amidines depolarized INS-1 cells and generated action potentials, accompanied by a decrease of membrane conductance. Simultaneously [Ca(2+)](i) increased, probably due to Ca(2+)-entry through voltage-dependent Ca(2+)-channels. At high concentrations, where inhibition of secretion was observed, ¿Ca(2+)(i) still rose upon application of the amidines, indicating an additional inhibitory pathway downstream to the elevation of ¿Ca(2+)(i). Even at high concentrations (100 microM), the amidines had no toxic effects on insulin secreting INS-1 cells.
Hartmann
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Chair of Pharmaceutical Chemistry, University of Freiburg, Hermann-Herder-Str. 9, D-79104, Freiburg, Germany.
Ullrich
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Hupfer
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Frahm
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AW
D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008564:Membrane Potentials / Q000187:drug effects; D026902:Potassium Channel Blockers; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D000578:Amidines; D007004:Hypoglycemic Agents; D007328:Insulin; D026902:Potassium Channel Blockers; D002118:Calcium