Structure-activity relationships among methoctramine-related polymethylene tetraamines. Chain-length and substituent effects on M-2 muscarinic receptor blocking activity.

Several polymethylene tetraamines related to methoctramine (1) were prepared and evaluated for their blocking activity on M-2 muscarinic receptors in guinea pig atria and ileum. It turned out that antimuscarinic potency depends on the following parameters: (a) nature of the substituent on both inner and outer nitrogens and (b) carbon chain length separating the inner nitrogens as well as the inner and outer nitrogens. Optimum activity at cardiac M-2 muscarinic receptors was associated with the chain lengths present in 1, that is, eight methylenes between the inner nitrogens and six methylenes between the inner and outer nitrogens. With regard to the substituents, replacement of the benzylic moiety of 1 by a 2-furyl or a 5-methyl-2-furyl nucleus resulted in enhanced potency toward cardiac M-2 muscarinic receptors. In fact, furtramine (18) and mefurtramine (19) proved to be more potent and more selective than 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, resulted in an increase in activity in both atria and ileum.