Synthesis and cannabinoid-1 receptor binding affinity of conformationally constrained analogs of taranabant.
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.
Kopka
Ihor E
IE
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Lin
Linus S
LS
Jewell
James P
JP
Lanza
Thomas J
TJ
Fong
Tung M
TM
Shen
Chun-Pyn
CP
Lao
Zhege J
ZJ
Ha
Sookhee
S
Castonguay
Laurie G
LG
Van der Ploeg
Lex
L
Goulet
Mark T
MT
Hagmann
William K
WK
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
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