title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Yiyan
authors.initials: Y
authors.lastname: Songyang
authors.affiliation: Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China. Electronic address: songjcwhu@163.com.
authors.forename: Jinchun
authors.initials: J
authors.lastname: Song
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D011743:Pyrimidines; D011799:Quinazolines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000612662:5,6,7,8-tetrahydroquinazoline; C000612661:6,7-dihydro-5H-cyclopenta(d)pyrimidine
keywords: 5,6,7,8-Tetrahydroquinazoline; 6,7-Dihydro-5H-cyclopenta[d]pyrimidine; Analgesic; Sigma-1 (σ(1)) receptor antagonists