Structure–activity relationships of methoctramine-relatedpolyamines as muscarinic antagonist: Effect of replacing theinner polymethylene chain with cyclic moieties

The aim of the present paper was to investigate the role of the octamethylene spacer of methoctramine (1) on the biological profile. Thus, this spacer was incorporated into a dianiline or dipiperidine moiety to determine whether flexibility and the basicity of the inner nitrogen atoms are important determinants of potency with respect to muscarinic receptors. The most potent compound was 4, which displayed, in the functional assays, a comparable potency at muscarinic M2 receptors with respect to 1, and, in the binding assays, a loss of potency and selectivity toward muscarinic M1 and M3 receptor subtypes. Both compounds were endowed with antinociceptive activity. Furthermore, in microdialysis tests in rat parietal cortex, they enhanced acetylcholine release most likely by antagonizing presynaptic muscarinic receptor subtypes.