Involvement of sigma 2 receptor on motor disorder

Sigma (σ) receptors are a well defined class of receptors present in CNS as well as in peripheral tissues. Pharmacological studies have identified two subtypes of σ receptors, σ1 and σ2. However, their endogenous ligands still remains unknown. Moreover, it has not been well defined which are the signal transduction pathways triggered by those receptors. Whereas the gene encoding the σ1 has been cloned and characterized, the molecular nature of the σ2 is still not clearly defined. From studies of the biology and function of σ receptors, evidence has been presented that σ receptor ligands may be useful in the treatment of psychosis and movement disorders and motor disturbances associated with Huntington’s chorea or Tourette’s syndrome and in Parkinson’s disease. Tourette syndrome is a childhood onset neurodevelopmental disorder characterized by hyperactivity disorder, multiple motor and vocal tics, attention deficit and/or obsessive-compulsive disorder. Hyperfunction or imbalance of the dopamine system, at cortico-striatal-thalamo-cortical (CSTC) level, has been documented in Tourette syndrome patients, based on various nuclear imaging studies, CSF analyses or postmortem studies. It has been demostrated that cocaine can inhibit NMDA-stimulated [3H]dopamine release from rat striata via σ2 receptors. So it can be postulated that a σ2 selective ligand could interact with this dopaminergic system. Moreover, Ibogaine aσ2 selective agonist, noncompetitively inhibited transport by dopamine transporter (DAT). In light of this, we focused our attention on the synthesis of σ2 selective ligand useful for the investigation of its pharmacological role on Tourette’s syndrome or several CNS disorders. Based on this idea, we recently synthetized a compound [SVR 14-3], structurally related to ibogaine, which resulted σ2 selective from binding studies, supported also by isolated organ tests. So we aim to examine the regulation of dopamine release induced by our compound.