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Sigma receptor ligands bind sigma-1 and sigma-2 receptors, two unrelated proteins that are not G protein-coupled. The sigma-1 receptor was cloned in 1996 and resembles a yeast sterol isomerase more than any known mammalian receptor. It resides mainly in the endoplasmic reticulum, and its 2016 crystal structure showed a trimer with one transmembrane helix per protomer. The gene for the sigma-2 receptor was identified in 2017 as transmembrane protein 97 (TMEM97). Cutamesine (SA4503) dihydrochloride, 4-IBP and pentoxyverine citrate are sigma-1 agonists, whereas S1RA and BD-1047 2HBr are sigma-1 antagonists. Siramesine is a sigma-2 agonist, and UMB24 a sigma-2 antagonist.
