Universal Template Approach to Drug Design:  Polyamines as Selective Muscarinic Receptor Antagonists

Abstract

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.

Structure−Activity Relationships of Methoctramine-Related Polyamines as Muscular Nicotinic Receptor Noncompetitive Antagonists. 2. Role of Polymethylene Chain Lengths Separating Amine Functions and of Substituents on the Terminal Nitrogen Atoms

“…1,3,4 The rationale for these structural modifications was based on the observation that 1, at micromolar concentrations, antagonizes nAChRs, hence providing the prospect of applying the universal template approach 5 to the design of polyamines as nAChR ligands. 1 The nAChR, a prototypical member of the superfamily of ligand-gated ion channels, is a heteropentameric transmembrane protein with the subunit stoichiometry R 2 γδ.…”

Polymethylene tetraamine backbone as template for the development of biologically active polyamines

“…4). 22 The insertion of one PBD moiety onto only one of the terminal nitrogen atoms of a tetraamine and diamine diamide backbone afforded 6 and 20, respectively, which displayed an affinity profile similar to that of methoctramine (2). This observation formed the basis to verify whether the position of the tricyclic moiety relative to the protonated terminal nitrogen atom may be responsible for receptor subtype selectivity.…”

“…Soon after, benextramine was shown to recognize other receptor systems, such as nicotinic 19 and muscarinic 20 receptors thus giving the basis for the development of the universal template approach 21,22 to the design of polyamines as selective ligands for different biological targets.…”

“…The assumption that a polyamine can be a universal template stands on the following: 22 it is known that a high percentage of homology exists not only within receptor subtypes but also among different receptor families, which may account for the difficulty in achieving receptor selectivity that remains one of the most fascinating challenges to medicinal chemists. Although receptor homology makes it inherently difficult to achieve receptor selectivity, it may be used indeed to design molecular entities that are able, in principle, to recognize different receptor systems.…”

“…This observation formed the basis to verify whether the position of the tricyclic moiety relative to the protonated terminal nitrogen atom may be responsible for receptor subtype selectivity. 22 To this end, homologues 25-27 and 28-30 of the monosubstituted tetraamine 6 and diamine diamide 20, respectively, bearing from two to four methylenes between the terminal nitrogen atom and the tricyclic group, were investigated. It turned out that the effect of lengthening the distance between the tricyclic moiety and the terminal nitrogen atom of either 6 or 20 was qualitatively similar for both muscarinic M 2 and M 3 receptors (Table III).…”