Development of benzophenone-alkyne bifunctional sigma receptor ligands.

Sigma (s) receptors are unique non-opioid binding sites that are associated with a broad range of disease states. Sigma-2 receptors provide a promising target for diagnostic imaging and pharmacological interventions to curb tumor progression. Most recently, the progesterone receptor (PGRMC1, 25 kDa) has been shown to have s2 receptor-like binding properties, thus highlighting the need to understand the biological function of an 18 kDa protein that exhibits s2-like photoaffinity labeling (denoted here as s2-18k) but the amino acid sequence of which is not known. In order to provide new tools for the study of the s2-18k protein, we have developed bifunctional s receptor ligands each bearing a benzophenone photo-crosslinking moiety and an alkyne group to which an azide-containing biotin affinity tag can be covalently attached through click chemistry after photo-crosslinking. Although several compounds showed favorable s2 binding properties, the highest affinity (2 nM) and the greatest potency in blocking photolabeling of s2-18k by a radioactive photoaffinity ligand was shown by compound 22. These benzophenone-alkyne s receptor ligands might therefore be amenable for studying the s2-18k protein through chemical biology approaches. To the best of our knowledge, these compounds represent the first reported benzophenone-containing clickable s receptor ligands, which might potentially have broad applications based on the plugging in of various tags.