Identification of Antagonists Selective for Sigma Receptor Subtypes that are Active In vivo.

σRs have been mischaracterized [2-4] and were initially thought to be opioid receptor subtypes [5]. They have been classified into two subtypes based on specific radioligand binding assays using [3H](+)pentazocine for σ1Rs and [3H]1,3-di-o-tolylguanidine ([3H]DTG), in the presence of (+)-pentazocine to mask the σ1R, for σ2Rs [6-11] (Table 1). The σ1R has already been cloned and is a 25-29 kDa intracellular chaperone protein composed of 223 amino acids [12-14]. In contrast, the [3H](+)-pentazocine-inaccessible σR, the σ2R, is an 18–21 kDa protein that has not yet been cloned. Until recently, there have been no reports of antagonists that are selective for either receptor subtype or that are active in vivo, probably because of the lack of reliable in vivo assays for σR subtypes. The paper by Katz et al. [1] finally identifies antagonists selective for σR subtypes [1] that are active in vivo.