title: Development of benzophenone-alkyne bifunctional sigma receptor ligands.
abstract: Sigma (σ) 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 σ2 receptor-like binding properties, thus highlighting the need to understand the biological function of an 18 kDa protein that exhibits σ2-like photoaffinity labeling (denoted here as σ2-18k) but the amino acid sequence of which is not known. In order to provide new tools for the study of the σ2-18k protein, we have developed bifunctional σ 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 σ2 binding properties, the highest affinity (2 nM) and the greatest potency in blocking photolabeling of σ2-18k by a radioactive photoaffinity ligand was shown by compound 22. These benzophenone-alkyne σ receptor ligands might therefore be amenable for studying the σ2-18k protein through chemical biology approaches. To the best of our knowledge, these compounds represent the first reported benzophenone-containing clickable σ receptor ligands, which might potentially have broad applications based on the "plugging in" of various tags.
authors.affiliation: Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, 1300 University Ave., Madison, WI 53706, USA.
authors.forename: Lian-Wang
authors.initials: LW
authors.lastname: Guo
authors.forename: Abdol R
authors.initials: AR
authors.lastname: Hajipour
authors.forename: Kerim
authors.initials: K
authors.lastname: Karaoglu
authors.forename: Timur A
authors.initials: TA
authors.lastname: Mavlyutov
authors.forename: Arnold E
authors.initials: AE
authors.lastname: Ruoho
mesh_terms: D000480:Alkynes / Q000737:chemistry* / Q000494:pharmacology*; D001577:Benzophenones / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D057930:Click Chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D006801:Humans; D008024:Ligands; D055668:Photochemical Processes; D017480:Receptors, sigma / Q000378:metabolism*
chemical_list: D000480:Alkynes; D001577:Benzophenones; D003432:Cross-Linking Reagents; D008024:Ligands; D017480:Receptors, sigma; C106107:sigma-2 receptor; C047723:benzophenone