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

Abstract

The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of ligands for different biological targets. As a matter of fact, the insertion of different pharmacophores onto the polymethylene tetraamine backbone can tune both affinity and selectivity for any given receptor. The application of this approach provided a prospect of modifying benextramine (1). structure to achieve specific recognition of muscarinic receptors that led to the discovery of methoctramine (2). which is widely used as a pharmacological tool for muscarinic receptor characterization. In turn, appropriate structural modifications performed on the structure of methoctramine led to the discovery of new polyamines endowed with high affinity and selectivity for (a). muscarinic receptor subtypes, (b). G(i) proteins, and (c). muscle-type nicotinic receptors. Thus, polyamines tripitramine (9) and spirotramine (33), among others, were designed, which were shown to be highly selective for muscarinic M(2) and M(1) receptors, respectively. Several polyamines have been discovered, which inhibit noncompetitively a closed state of the nicotinic receptor. These ligands, such as 66, resulted in important tools for elucidating the mode and site of interaction of polyamines with the ion channel. It was discovered that reducing the flexibility of the diaminohexane spacer of methoctramine led to polyamines, such as 70, which are endowed with a biological profile significantly different from that of the prototype. Most likely, tetraamine (70) is a potent activator of G(i) proteins. Finally, the universal template approach formed the basis for modifying benextramine (1) structure to the design of ligands, which display affinity for acetylcholinesterase and muscarinic M(2) receptors. Thus, these polyamines, such as caproctamine (78), could have potential in the investigation of Alzheimer disease.

Polyamines and apoptosis

“…A potential way out of the dilemma, though not a simple way, is perhaps the design and synthesis of structural analogues which mimic polyamine functions, but have more selective binding affinities than the natural polyamines. Melchiorre and his colleagues [138] have demonstrated that it is in principle possible to modify the polyamine backbone, and to attach substituents in such a way to the polyamine structure that compounds are obtained, which bind selectively to certain membrane receptor proteins and enzymes. This approach should also be applicable to regulators of growth, to regulators of the cell cycle and to apoptotic factors.…”

Medical Applications of Macrocyclic Polyamines

“…They have long been associated with cell growth and cancer, and continued to be molecules that hold fascination for biologists, chemists, molecular biologists and clinical researchers [39]. Polyamines may represent a universal template in the receptor recognition process [40]. Various polyamine Screening of compound libraries, including corporate libraries with large structural diversities and those with similar structures generated from combinatorial synthesis, is a powerful approach for developing RNA-binding compounds [32].…”

Memoquin: A Multi-Target–Directed Ligand as an Innovative Therapeutic Opportunity for Alzheimer's Disease

“…All these results have constituted the premise for medicinal chemists to design a new class of dual-binding site inhibitors thatable to simultaneously interact with the two sites-might alleviate the cognitive deficit in AD and, more importantly, address the etiology of the disease. 24 -26 In view of early evidence that polyamineamides were versatile molecular scaffolds suitable for designing com- pounds able to recognize multiple protein targets, 27 we considered the possibility of modifying the structure of 1 to obtain a multi-target-directed ligand (MTDL). 28 In addition to the cholinergic properties, we aimed to add to caproctamine another activity beneficial for AD, such as the antioxidant property.…”