Synthesis and biological evaluation of novel 6,7-dihydro-5H-cyclopenta[d]pyrimidine and 5,6,7,8-tetrahydroquinazoline derivatives as sigma-1 (σ1) receptor antagonists for the treatment of pain.

The synthesis and biological evaluation of new series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine and 5,6,7,8-tetrahydroquinazoline derivatives as selective sigma-1 receptor (σ1R) antagonists are reported. The receptor affinities of new compounds were evaluated in vitro in σ1 and σ2 receptor binding assays. The structure-active relationship study leads us to the most promising compound: 2-(4-chlorophenyl)-4-(3-(4-methylpiperidin-1-yl)propoxy)-5,6,7,8-tetra-hydroquinazoline (33). Compound 33 has exerted nanomolar affinity for σ1R (Kiσ1=15.6 nM) and high σ1/σ2 selectivity (Kiσ2 >2000 nM), and identified to be a σ1R antagonist. In animal model, compound 33 exhibited dose dependent anti-nociceptive effects in the formalin test. These results suggest that compound 33 could be a potent analgesic for pain treatment.