title: Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists.
abstract: Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, MSD Ltd, Newhouse, Lanarkshire, UK.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Moir
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yoshiizumi
authors.forename: Jim
authors.initials: J
authors.lastname: Cairns
authors.forename: Phillip
authors.initials: P
authors.lastname: Cowley
authors.forename: Morag
authors.initials: M
authors.lastname: Ferguson
authors.forename: Fiona
authors.initials: F
authors.lastname: Jeremiah
authors.forename: Takao
authors.initials: T
authors.lastname: Kiyoi
authors.forename: Richard
authors.initials: R
authors.lastname: Morphy
authors.forename: Jason
authors.initials: J
authors.lastname: Tierney
authors.forename: Grant
authors.initials: G
authors.lastname: Wishart
authors.forename: Mark
authors.initials: M
authors.lastname: York
authors.forename: James
authors.initials: J
authors.lastname: Baker
authors.forename: Jean E
authors.initials: JE
authors.lastname: Cottney
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Houghton
authors.forename: Petula
authors.initials: P
authors.lastname: McPhail
authors.forename: Andrew
authors.initials: A
authors.lastname: Osprey
authors.forename: Glenn
authors.initials: G
authors.lastname: Walker
authors.forename: Julia M
authors.initials: JM
authors.lastname: Adam
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D053961:Azabicyclo Compounds; D001643:Bridged Bicyclo Compounds; D007211:Indoles; D010879:Piperazines; D043884:Receptor, Cannabinoid, CB1; C030374:indole