title: CGS 9343B, a novel, potent, and selective inhibitor of calmodulin activity.
abstract: 1,3-Dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]- benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-o ne (1:1) maleate was synthesized in six steps from methyl anthranilate and designated CGS 9343B. CGS 9343B inhibited calmodulin-stimulated cAMP phosphodiesterase activity with an IC50 value of 3.3 microM. CGS 9343B was 3.8 times more potent than trifluoperazine (IC50 = 12.7 microM) as an inhibitor of calmodulin activity. CGS 9343B did not inhibit protein kinase C activity at concentrations up to 100 microM, whereas trifluoperazine inhibited protein kinase C activity with an IC50 value of 43.9 microM. CGS 9343B weakly displaced [3H]spiperone from postsynaptic dopamine receptors with an IC50 value of 4.8 microM while the value for trifluoperazine, a potent antipsychotic agent, was 0.018 microM. It is concluded that CGS 9343B is a novel, potent, and selective inhibitor of calmodulin activity. Unlike trifluoperazine, CGS 9343B does not inhibit protein kinase C activity and does not possess potential antidopaminergic activity.
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002417:Cattle; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D002147:Calmodulin; D011954:Receptors, Dopamine; C052087:CGS 9343B; D014268:Trifluoperazine; D013134:Spiperone; D011493:Protein Kinase C; D015105:3',5'-Cyclic-AMP Phosphodiesterases