From the universal template strategy to multi-site-directed ligands for the treatment of Alzheimer’s disease

From the universal template strategy to multi-site-directed ligands for the treatment of Alzheimer’s disease Carlo Melchiorre, Department of Pharmaceutical Sciences, Alma Mater Studiorum – University of Bologna, Via Belmeloro 6, 40139 Bologna, Italy Alzheimer’s disease (AD), the most common cause of dementia, is a complex neurological affection that is characterized by loss of memory and progressive deficits in different cognitive domains and by massive deposits of aggregated proteins to form the intracellular neurofibrillary tangles and the extracellular senile plaques. Even if the primary cause of AD is still speculative, early amyloid-beta peptide (Abeta) aggregates are thought to be mainly responsible for the devastating clinical effects of the disease. Although, at present, the most followed approach to identify AD drugs is the amyloid hypothesis, significant research has been also devoted to the role of free radical formation, oxidative cell damage, and inflammation in the pathogenesis of AD, providing new promising targets and validated animal models. Despite the large amount of basic research carried out into the causes of the disease, AD still represents a formidable challenge to medicinal chemists because progress toward effective pharmacological treatments has been remarkably slow. The multi-factorial nature of AD forms the basis of the growing consensus that the winning approach for the future treatment of the disease will be the therapy with drugs that are able to hit different selected targets. Following this rationale much effort has been devoted to the discovery of multi-site-directed ligands (MTDLs) against AD, i.e., single molecules that can exhibit multiple pharmacological properties simultaneously, such as cholinergic transmission enhancement and inhibition of Abeta accumulation or oxidative stress, leading to a synergic effect. To this end, different design strategies in which distinct pharmacophores of different drugs have been combined in the same structure leading to hybrid molecules have been applied. In principle, each pharmacophore of these new drugs should retain the ability to interact with its specific site(s) on the target and consequently to produce specific pharmacological responses that taken together should block or hopefully cure the neurodegenerative process leading to AD. To design MTDLs for the treatment of AD we have applied the universal template strategy, which foresees that a polyamine backbone may represent a master key (“passe-partout”) in the drug-target recognition process. In other words, a polyamine backbone can be considered a universal template on which suitable groups (pharmacophores) can be mounted to achieve selectivity for any given protein target. This working hypothesis derives from the consideration that the backbone of a protein has only a structural role whereas the lateral chains play a major role in drug-protein target binding through the interaction of aspartate, glutamate, and aromatic residues with cationic ligands by way of a cation-anion or a cation-pi interaction. Considering that proteins may bear several carboxylate and/or aromatic residues somewhere in their structure, in principle, it is possible to design a lead compound having a polyamine backbone which is able to recognize multiple anionic sites of a given protein. Thus, such a ligand may interact with all proteins, provided that the distance separating the amine functions of the ligand fits the distance between the carboxylate or aromatic residues of the protein. An appropriate modification of the chain length separating the nitrogens of a polyamine might give rise to an increase of affinity, whereas the insertion of N-substituents might improve the selectivity as well as the affinity by increasing the overall number of contacts between a drug and a protein. The application of this strategy, leading to the development of Memoquin, will be discussed.