From iloperidone to new sigma-1 receptors agonists: a structure-based approach.

Huntington's disease (HD) is a hereditary condition caused by a mutation in the HTT gene, resulting in the progressive degeneration and death of neurons in certain areas of the brain. Unfortunately, there are currently no effective treatments capable of halting or preventing the onset of this debilitating disease. However, an increasing number of research suggests that the sigma-1 receptor (σ1R) may play a role in the management of various neurodegenerative disorders, including HD1. The σ1R is a relatively small and poorly understood membrane receptor found in the central nervous system. Its three-dimensional structure has recently been elucidated through X-ray crystallography, and it responds to various synthetic ligands, such as (+)-pentazocine (an agonist) and haloperidol (an antagonist). Studies have shown that agonists possess neuroprotective properties against neurodegenerative diseases. Nevertheless, the structural mechanisms underlying agonism or antagonism at the σ1R are not fully understood. Generally, the overall conformation of the receptor when bound to an agonist is similar to that when bound to an antagonist, except for a shift in the α4 helix by approximately 1.8Å2. This shift likely contributes to the agonists' ability to decrease the oligomeric state of the protein and can serve as a discriminative factor for agonist classification. Through structure-based computational methods, we designed new Iloperidone analogues as potential σ1R agonists. Indeed, very recently, a high binding affinity for σ1R of the antipsychotic Iloperidone has been demonstrated3,4. From our computational studies, including cross-docking procedures and molecular dynamics simulations5, the pharmacophoric groups have emerged. In detail, the most stable interactions are established by the nitrogen atom of the piperidine ring of Iloperidone, which is positively charged at physiological pH. This charge allows the molecule to interact with the Phe107 of protein and the negatively charged Glu172 residue. Starting to these data, the chemical structure of this antipsychotic drug has been modified applying a scaffold hopping approach, in order to obtain a pronounced and selective agonist of the σ1R. We synthesized new small molecules that retained the piperidine core and replacing the benzoisoxazole ring (responsible for a generic π-π interaction) with oximes. Additionally, we have functionalized the oxygen atom of the oxime group to enhance steric hindrance between the α5 and α4 helices, with shifts in the latter. Biological assay data will be presented and discussed to further elucidate the efficacy of these novel compounds.