Conformational analysis and receptor docking of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (taranabant, MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist.
X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.
Lin
Linus S
LS
Departments of Medicinal Chemistry, Molecular Systems, Process Research, and Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
Ha
Sookhee
S
Ball
Richard G
RG
Tsou
Nancy N
NN
Castonguay
Laurie A
LA
Doss
George A
GA
Fong
Tung M
TM
Shen
Chun-Pyn
CP
Xiao
Jing Chen
JC
Goulet
Mark T
MT
Hagmann
William K
WK
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002478:Cells, Cultured; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D012015:Reference Standards; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D000577:Amides; 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