Some studies on cytisine and its methylated derivatives.

1. In mice cytisine hydrochloride is less toxic intravenously than nicotine hydrogen tartrate, but more toxic by intraperitoneal or oral administration. Compared with cytisine, caulophylline hydrogen iodide is one-fifth to one-tenth as toxic and caulophylline methiodide is less than one-thirtieth as toxic.2. The surprising low oral toxicity of cytisine and nicotine may be ascribed to the method of administration; if the drug is placed directly in the stomach there is no possibility of absorption through buccal mucous membranes.3. The peripheral effects of nicotine, cytisine and caulophylline are similar, though on some preparations those of nicotine last longer. In most tests cytisine is active in doses from a quarter to three-quarters of those of nicotine, caulophylline in doses from 10 to 20 times those of cytisine. Caulophylline methiodide is virtually inactive.4. Cytisine and caulophylline may differ from nicotine in their central effects.5. Cytisine and caulophylline are active as the cations. The pKa of cytisine is 7.92 and that of caulophylline is 7.04; the difference accounts, in part, for the weaker activity of caulophylline. The caulophylline ion is generally one-sixth to one-third as active as the cytisine ion.6. The introduction of the second methyl group to form the quaternary salt does not appear to cause a dramatic change in the conformation of the molecule. Caulophylline methiodide appears to be feebly active because it has feeble affinity.