Structure_Activity Relationships among Methoctramine-Related Polymethylene Tetramine. Chain Length and Substituent Effects on M2 Muscarinic Receptor Blocking Activity.

Several polymethylene tetraamines related to methoctramine (1) were prepared and evaluated for their blockingactivity on M-2 muscarinic receptors in guinea pig atria and ileum. It turned out that antimuscarinic potency dependson the following parameters: (a) nature of the substituent on both inner and outer nitrogens and (b) carbon chainlength separating the inner nitrogens as well as the inner and outer nitrogens. Optimum activity at cardiac M-2muscarinic receptors was associated with the chain lengths present in 1, that is, eight methylenes between the innernitrogens and six methylenes between the inner and outer nitrogens. With regard to the substitueats, replacementof the benzylic moiety of 1 by a 2-fury1 or a 5-methyl-2-fury1 nucleus resulted in enhanced potency toward cardiacM-2 muscarinic receptors. In fact, furtramine (18) and mefurtramine (19) proved to be more potent and more selectivethan 1. Moreover, N-methylation of the four nitrogens of 1 gave different effects: methylation of the outer nitrogens,giving 22, caused a significant decrease in activity whereas methylation of the inner nitrogens, yielding 23, resultedin an increase in activity in both atria and ileum.