RT Journal Article
SR Electronic
T1 Divergent Cytotoxic and Metabolically Stimulative Functions of Sigma-2 Receptors: Structure-Activity Relationships of 6-Acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[<em>d</em>]oxazol-2(3<em>H</em>)-one (SN79) Derivatives
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 272
OP 281
DO 10.1124/jpet.118.253484
VO 368
IS 2
A1 Hilary E. Nicholson
A1 Walid F. Alsharif
A1 Anthony B. Comeau
A1 Christophe Mesangeau
A1 Sebastiano Intagliata
A1 Marco Mottinelli
A1 Christopher R. McCurdy
A1 Wayne D. Bowen
YR 2019
UL http://jpet.aspetjournals.org/content/368/2/272.abstract
AB Sigma-2 receptors, recently identified as TMEM97, have been implicated in cancer and neurodegenerative disease. Structurally distinct sigma-2 receptor ligands induce cell death in tumor cells, linking sigma-2 receptors to apoptotic pathways. Recently, we reported that sigma-2 receptors can also stimulate glycolytic hallmarks, effects consistent with a prosurvival function and upregulation in cancer cells. Both apoptotic and metabolically stimulative effects were observed with compounds related to the canonical sigma-2 antagonist SN79. Here we investigate a series of 6-substituted SN79 analogs to assess the structural determinants governing these divergent effects. Substitutions on the benzoxazolone ring of the core SN79 structure resulted in high-affinity sigma-2 receptor ligands (Ki = 0.56–17.9 nM), with replacement of the heterocyclic oxygen by N-methyl (producing N-methylbenzimidazolones) generally decreasing sigma-1 affinity and a sulfur substitution (producing benzothiazolones) imparting high affinity at both subtypes, lowering subtype selectivity. Substitution at the 6-position with COCH3, NO2, NH2, or F resulted in ligands that were not cytotoxic. Five of these ligands induced an increase in metabolic activity, as measured by increased reduction of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) in human SK-N-SH neuroblastoma cells, further supporting a role for sigma-2 receptors in metabolism. Substitution with 6-isothiocyanate resulted in ligands that were sigma-2 selective and that irreversibly bound to the sigma-2 receptor, but not to the sigma-1 receptor. These ligands induced cell death upon both acute and continuous treatment (EC50 = 7.6–32.8 μM), suggesting that irreversible receptor binding plays a role in cytotoxicity. These ligands will be useful for further study of these divergent roles of sigma-2 receptors.