title: Decahydroquinoline amides as highly selective CB2 agonists: role of selectivity on in vivo efficacy in a rodent model of analgesia.
abstract: A novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain. A moderately selective CB2 agonist was active in this model. A CB2 agonist lacking functional CB1 activity was inactive in this model despite high in vivo exposure both peripherally and centrally.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point PA, United States. peter_manley@merck.com
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Manley
authors.forename: Amy
authors.initials: A
authors.lastname: Zartman
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Paone
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
authors.forename: Darrell A
authors.initials: DA
authors.lastname: Henze
authors.forename: Kimberly
authors.initials: K
authors.lastname: Della Penna
authors.forename: Reshma
authors.initials: R
authors.lastname: Desai
authors.forename: Michael D
authors.initials: MD
authors.lastname: Leitl
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: White
authors.forename: Suzie
authors.initials: S
authors.lastname: Yeh
authors.forename: Mark O
authors.initials: MO
authors.lastname: Urban
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
authors.forename: B Wesley
authors.initials: BW
authors.lastname: Trotter
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010146:Pain / Q000188:drug therapy; D011804:Quinolines / Q000737:chemistry*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000700:Analgesics; D011804:Quinolines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C037219:quinoline