title: Synthesis and cannabinoid-1 receptor binding affinity of conformationally constrained analogs of taranabant.
abstract: The design, synthesis, and binding activity of ring constrained analogs of the acyclic cannabinoid-1 receptor (CB1R) inverse agonist taranabant 1 are described. The initial inspiration for these taranabant derivatives was its conformation 1a, determined by (1)H NMR, X-ray, and molecular modeling. The constrained analogs were all much less potent than their acyclic parent structure. The results obtained are discussed in the context of a predicted binding of 1 to a homology model of CB1R.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Ihor E
authors.initials: IE
authors.lastname: Kopka
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.forename: James P
authors.initials: JP
authors.lastname: Jewell
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lanza
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Chun-Pyn
authors.initials: CP
authors.lastname: Shen
authors.forename: Zhege J
authors.initials: ZJ
authors.lastname: Lao
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Castonguay
authors.forename: Lex
authors.initials: L
authors.lastname: Van der Ploeg
authors.forename: Mark T
authors.initials: MT
authors.lastname: Goulet
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000577:Amides; D019440:Anti-Obesity Agents; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide