SYA 013 analogs as moderately selective sigma-2 (σ2) ligands: Structure-affinity relationship studies

Abstract Several lines of evidence suggest that selective sigma-2 (σ 2 ) ligands might be useful for the treatment of solid tumors. However, very few selective σ 2 ligands have been identified. This study was aimed at identifying new selective σ 2 receptor ligands using a previously identified agent, SYA 013 as a lead. Four groups, homopiperazine, piperazine, tropane and selected oxime analogs of the homopiperazines were identified, synthesized and subsequently screened at the σ 1 and σ 2 receptors. The results demonstrate that these scaffolds can be modified to obtain selective σ 2 receptor ligands. 1-(5-Chloropyridin-2-yl)-4-(3-((4-fluorophenyl)thio)propyl)-1,4-diazepane, 7 and 3-(4-chlorophenyl)-8-(3-((2-fluorophenyl)thio)propyl)-8-azabicyclo[3.2.1]octan-3-ol, 21 were identified as the highest binding affinity ligands (σ 2 Ki  = 2.2 nM) and (4-(4-(5-chloropyridin-2-yl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-butan-1-one oxime, 22 as a high affinity and the most selective ligand for the σ 2 receptor (σ 1 Ki /σ 2 Ki  = 41.8).