Muscarinic activity of some secondary and tertiary amines and quaternary ammonium salts structurally related to oxotremorine

A number of secondary and tertiary amines as well as quaternary ammonium compounds, obtained by structural modification of the amino group of oxotremorine (1) and its acetamide analogue (14), were investigated for muscarinic and antimuscarinic activity in vivo and in vitro. For the quaternary ammonium analogues, decrease of in vitro muscarinic potency is well correlated with increase of the size of the quaternary ammonium group, as estimated from increments in apparent molal volumes. A similar decrease of muscarinic potency with increasing substitution at the nitrogen atom is generally observed for the secondary and tertiary amines. For the latter the reduction in muscarinic activity appears to be due to loss of efficacy, since the higher homologues are partial agonists or antagonists. There is a highly significant correlation between muscarinic activity in vitro and central tremorogenic activity of the tertiary amines.