Steroid binding at sigma receptors: CNS and immunological implications.

The sigma receptor has been suggested to be the mediator of the psychomimetic effects induced by certain benzomorphan opioids and phencyclidine. Potent sigma receptor ligands include haloperidol and other 'atypical' potential antipsychotic drugs. The sigma receptor is found in the central nervous system and also in the immune and endocrine systems. Gonadal and adrenal steroids such as progesterone, testosterone, deoxycorticosterone and corticosterone were found to be competitive inhibitors of binding of the sigma receptor ligand [3H] d-SKF-10,047. The sigma receptor is not the traditionally recognized cytosolic progesterone receptor and is found in crude membrane fractions. Results from molecular modelling using geometric fitting and electrostatic potential calculations suggested that the molecular skeleton of steroid hormones shares common features with prototypic sigma ligands such as d-SKF-10,047 and that the oxygen of the C-20 carbonyl group on these steroids may represent a critical 'pharmacophore' for their interactions with sigma receptors. Comparison of the affinities of steroids at sigma receptors with their efficacies is an anti-inflammatory test yielded a striking qualitative correlation. Taken Taken together these results suggest that sigma receptors may mediate certain aspects of steroid-induced mental disturbances and alterations in immune function.