Bispecific Sigma1R-Antagonist/MOR-Agonist Compounds for Pain

Recent research has significantly advanced an understanding of sigma receptors, which consist of two distinct subtypes designated as S1R and S2R (s1R and s2R gene products, respectively). Both subtypes have recently been cloned and their crystal structures have been published. As a result, highly selective S1R and S2R agonist and antagonist ligands are now available. Unlike the confusion generated from prior use of non-selective 'sigma' compounds, these tool compounds have begun to add clarity about the function of sigma receptors in health and disease.  The discovery of compounds with high-affinity (nM range) S1R/S2R or S2R/S1R subtype selectivity (>100-fold), and selectivity over off-target sites (>1,000-fold) has brought the study of sigma receptor pharmacology into the modern era. Computer modeling has contributed to a better understanding of the binding processes, structural requirements for chemical synthesis, and potential therapeutic uses. Several lines of evidence converge on pain as a therapeutic target for S1R-antagonists (as single mechanism or as part of a multi-mechanistic approach). We highlight here some compounds reported over the past few years that have promise for use as analgesics, specifically some mono-mechanistic S1R-antagonists, and some that are 'bispecific', i.e., have more than one mechanism of action, for example, complementary action of the mu-opioid receptor (MOR). We concentrate on some compounds that are further along in development, in particular, some of the bispecific S1R-antagonist/MOR-agonist compounds.