From Iloperidone to new Sigma1 agonists: a structure-based approach for Huntington's disease treatment.

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 HD. 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 suggests that knockdown or antagonism of the σ1R has analgesic effects, while agonists have been shown to 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 helix. Probably, this shift is responsible for the tendency of agonists to decrease the oligomeric state of the protein. Through structure-based computational methods, we aim to design new small molecules as σ1R modulators. Indeed, very recently, a high binding affinity for the σ1R of the antipsychotic Iloperidone has been demonstrated. From our early studies, 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 will be modified applying a scaffold hopping approach, in order to obtain a pronounced and selective agonist of the σ1R.