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.