UNIVERSAL TEMPLATE APPROACH TO DRUG DESIGN - POLYAMINES AS SELECTIVE MUSCARINIC RECEPTOR ANTAGONISTS

The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of new selectiv e 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 (M-2) and ileum (M-3) and by binding assays in rat cortex (M-1), heart (M-2), submaxillary gland (M-3), and NG 108-1 5 cells (M-4). 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-trip itramine (17) was able to discriminate significantly M-1 and M-2 recep tors versus the other subtypes, and in addition it was 100-fold more l ipophilic than the lead compound tripitramine. Compound 14 (tripinamid e), in which the tetraamine backbone was transformed into a diamine di amide one, retained high affinity for muscarinic subtypes, displaying a binding affinity profile (M-2 > M-1 > M-4 > M-3) qualitatively simil ar to that of tripitramine. Both these ligands, owing to their improve d lipophilicity relative to tripitramine and methoctramine, could serv e as tools in investigating cholinergic functions in the central nervo us system. Furthermore, notwithstanding the fact that the highest affi nity was always associated with muscarinic M-2 receptors, for the firs t time polyamines were shown to display high pA(2) values also toward muscarinic M-3 receptors.