Search

The aporphine alkaloids (+)-dicentrine and (+)-bulbocapnine are non-planar molecules lacking features normally associated with DNA binding by intercalation or minor groove binding. Surprisingly, dicentrine showed significant activity as a topoisomerase II (EC 5.99.1.3) inhibitor and also was active in a DNA unwinding assay. The DNA unwinding suggests DNA intercalation, which could explain the inhibition of topoisomerase II. Bulbocapnine, which differs from dicentrine only by the presence of a hydroxyl group at position 11 and the absence of a methoxyl group at position 9, was inactive in all assays. Molecular modeling showed that dicentrine can attain a relatively planar conformation, whereas bulbocapnine cannot, due to steric interaction between the 11-hydroxyl group and an oxygen of the methylenedioxy ring. These observations suggest that dicentrine is an “adaptive” DNA intercalator, which can bind DNA only by adopting a somewhat strained planar conformation. The requirement of a suboptimal conformation to achieve DNA binding appears to make dicentrine a weaker topoisomerase II inhibitor than the very planar oxoaporphine alkaloid liriodenine. These results suggest that it may be possible to modulate DNA binding and biologic activity of drugs by modifications affecting their ability to adopt planar conformations.

Rats were rendered catatonic by bulbocapnine and by audiogenic seizures. The glycogen content of the brain fell by approximately 14 per cent in both experimental situations. All parts of the brain lost glycogen, the ‘free’ glycogen fraction being predominantly affected. Brain glucose content rose in both forms of catatonia. In that due to audiogenic seizures, an early rise in the lactic acid content of the brain also occurred but lactic acid was unaffected in the early stages of bulbocapnine catatonia. Adrenal demedullation abolished the hyperglycaemic action of bulbocapnine. It reduced, but did not abolish, the effect of the drug on the glucose content of brain.

Using a modification of the spectrophotofluorometric method of Shore, Burkhalter and Cohn, an inhibition of diamine oxidase by bulbocapnine, using histamine as a substrate, has been demonstrated. The mechanism of the inhibition is competitive, as indicated by Lineweaver-Burke and Hunter-Downs plots. Pyridoxal phosphate was capable of antagonizing the inhibition by bulbocapnine of dialyzed hog kidney diamine oxidase. The possible involvement of a histaminergic mechanism in experimental catatonia is discussed.

It has been demonstrated that mescaline enhances histamine responses on rat blood pressure and on the guinea pig ileum. On the other hand, papaverine and bulbocapnine were found to potentiate the effects of histamine on the permeability of the capillary vessels of guinea pigs ; moreover, papaverine when injected with histamine or histidine develops a catatonic state in mice. At concentrations of 1 × 10 −5 and 1 × 10 −4 M, papaverine and mescaline inhibit the histaminolytic power of diamine oxidase. It is suggested that these effects of papaverine, mescaline, and bulbocapnine are mediated through an inhibition of histaminolysis, which in turn depends on the 4-methoxyphenylethylamine residue of these drugs.