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-5 H -cyclopenta[ d ]pyrimidine and 5,6,7,8-tetrahydroquinazoline derivatives as selective sigma-1 receptor ( σ 1 R) antagonists are reported. The receptor affinities of new compounds were evaluated in vitro in σ 1 and σ 2 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 σ 1 R ( K i σ 1 = 15.6 nM) and high σ 1 / σ 2 selectivity ( K i σ 2 >2000 nM), and identified to be a σ 1 R 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. [ABSTRACT FROM AUTHOR]