Structure-activity relationships among methoctramine-related polymethylene tetraamines. 3. Effect of the four nitrogens on M2 muscarinic blocking activity as revealed by symmetrical and unsymmetrical polyamines.

Several polymethylene tetraamines related to methoctramine (1) were synthesized and evaluated for their blocking activity on M2 and M3 muscarinic receptors of guinea pig left atria and ileum, respectively. In addition, the role of the number of basic nitrogens on activity was also examined. To this end, a series of polyamines (2-7), incorporating one, two or three fewer nitrogens than methoctramine, were synthesized. Furthermore, diamine diethers (8 and 9) and diamine diamides (10 and 11) were investigated to evaluate the role on affinity of the inner and the outer nitrogens of methoctramine. It was found that the presence of four nitrogens is necessary for optimum activity. The effect of benzylation of inner and outer nitrogens of methoctramine allowed the conclusion that optimum activity is associated with four secondary amine functions. The possible significance of the interaction of the four basic nitrogens of tetraamines with four anionic sites of M2 muscarinic receptors is discussed.