Bolognesi_1998_J.Med.Chem_41_4150

The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of new selective muscarinic ligands. Tetraamines 4-7 and 16-20 and diamine diamides 8-15 were synthesized, and their pharmacological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig left atrium (M2) and ileum (M3) and by binding assays in rat cortex (M1), heart (M2), submaxillary gland (M3), and NG 108-15 cells (M4). It has been confirmed that appropriate substituents on the terminal nitrogens of a tetraamine template can tune both affinity and selectivity for muscarinic receptors. The novel tetraamine C-tripitramine (17) was able to discriminate significantly M1 and M2 receptors versus the other subtypes, and in addition it was 100-fold more lipophilic than the lead compound tripitramine. Compound 14 (tripinamide), in which the tetraamine backbone was transformed into a diamine diamide one, retained high affinity for muscarinic subtypes, displaying a binding affinity profile (M2 > M1 > M4 > M3) qualitatively similar to that of tripitramine. Both these ligands, owing to their improved lipophilicity relative to tripitramine and methoctramine, could serve as tools in investigating cholinergic functions in the central nervous system. Furthermore, notwithstanding the fact that the highest affinity was always associated with muscarinic M2 receptors, for the first time polyamines were shown to display high pA2 values also toward muscarinic M3 receptors.