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

Carlo Melchiorre, Alessandra Antonello, Rita Banzi, Maria Laura Bolognesi, Anna Minarini, Michela Rosini, Vincenzo Tumiatti

Research output: Contribution to journalArticlepeer-review


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) Gi 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 M2 and M1 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 Gi 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 M2 receptors. Thus, these polyamines, such as caproctamine (78), could have potential in the investigation of Alzheimer disease.

Original languageEnglish
Pages (from-to)200-233
Number of pages34
JournalMedicinal Research Reviews
Issue number2
Publication statusPublished - Mar 2003


  • Acetylcholinesterase
  • G proteins
  • Muscarinic receptors
  • Nicotinic receptors
  • Polyamines
  • Universal template

ASJC Scopus subject areas

  • Organic Chemistry
  • Pharmacology
  • Medicine(all)


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