From iloperidone to new sigma-1 receptor agonists using a structure-based approach.

Huntington's disease (HD) is an autosomal dominant disorder caused by a mutation in the HTT gene, which progressively leads neurons in parts of the brain to break down and die. Unfortunately, to date there are no effective treatments that can stop or prevent the onset of this devastating disease. However, recent and growing numbers of studies are showing how the sigma-1 receptor (σ1R) may be implicated in the control of several neurodegenerative disorders, including HD1. The σ1R is a small and poorly understood membrane receptor expressed in the central nervous system, whose 3D structure has been recently determined by X-ray crystallography and responding to different synthetic ligands such as (+)-pentazocine (agonist) and haloperidol (antagonist). Substantial evidence has shown that agonists have neuroprotective activity in neurodegenerative diseases. Nevertheless, the structural basis for agonism or antagonism on σ1R is largely unknown. In general, the overall conformation of the receptor bound to the agonist crystallizes similarly to that bound to the antagonist, except for a shift of about 1.8Å in the α4 helix2. Probably, this shift is responsible for the tendency of agonists to decrease the oligomeric state of the protein and can be used as a discriminator for classification into agonist. 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. After that, we functionalized the oxygen atom of the oxime group, in order to increase the steric encumbrance between α5 and α4 helixes, with shifts of the latter. The data coming from the biological assays will be shown and discussed.