title: Design, synthesis and biological evaluation of piperazine analogues as CB1 cannabinoid receptor ligands.
abstract: After the CB1 receptor antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. Several series of urea, carbamate, amide, sulfonamide and oxalamide derivatives based on 1-benzhydrylpiperazine scaffold were synthesized and tested for CB1 receptor binding affinity. The SAR studies to optimize the CB1 binding affinity led to the potent urea derivatives. After the additional SAR studies to optimize the substituents of diphenyl rings, the combination of 2-chlorophenyl and 4-chlorophenyl turned out to be the most potent scaffold. The CB2 binding affinity assay as well as functional assay was also conducted on these compounds. Herein we wish to introduce several novel CB1 antagonists with IC(50) values less than 100 nM for the CB1 receptor binding.
authors.affiliation: Small Molecule Group, Central Research Institute, Green Cross Corporation, 341 Bojeong-dong, Giheung-gu, Yongin, Gyunggi-do 446-799, Republic of Korea.
authors.forename: Kwang-Seop
authors.initials: KS
authors.lastname: Song
authors.forename: Sung-Han
authors.initials: SH
authors.lastname: Lee
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Chun
authors.forename: Jong Yup
authors.initials: JY
authors.lastname: Kim
authors.forename: Myung Eun
authors.initials: ME
authors.lastname: Jung
authors.forename: Kwangwoo
authors.initials: K
authors.lastname: Ahn
authors.forename: Soo-Un
authors.initials: SU
authors.lastname: Kim
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Jinhwa
authors.initials: J
authors.lastname: Lee
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010879:Piperazines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000077489:Piperazine