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

Abstract

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.

Probing the Interaction of SR141716A with the CB1 Receptor

“…4, B and C. The present SR141716A binding mode appeared to be in good agreement not only with the results from the present mutation studies but also the results of mutation studies previ- ously reported by others (6,14,15,17,31 42 . In agreement, the structure-activity relationships and affinity studies of SR141716A and its derivatives with the CB1 receptor demonstrated the importance of the substituent on the N1-, C3-, and C5-positions (34 -36).…”

“…In support, it was well established that TM2/TM3/TM7 stabilization was important for the inactive state of the family A GPCRs (40,41 (31).…”

“…We estimated the contact numbers between SR141716A and the residues potentially involved in SR141716A binding based upon the results from this study (Table 1) as well as from the previous studies (6,14,15,17,31 6.51 , which were selected based upon the results from this study. Thus, the best SR141716A pose was determined such that the number of interactions between SR141716A and the ligand contact residues was high (favorable), whereas the number of interactions between SR141716A and the ligand noncontact residues was low (disfavorable).…”

“…We employed the MD simulation approach carefully guided by the results of the mutational studies reported previously (6,14,15,17,31) and presented in this study. Thus, our SR141716A-binding model was a dynamic model, where the binding mode of SR141716A was dynamically identified as the ligand moved within the binding pocket as a result of a long MD simulation performed in a lipid bilayer.…”

Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists

“…4A). The three compounds of interest were manually docked into the human CB 1 R model, taking into account the binding affinity data of rimonabant and other inverse agonists on CB 1 R mutants, such as W279A (Sitkoff et al, 2011) and S383A (Kapur et al, 2007;Lin et al, 2008). Figure 4 depicts the putative binding modes of rimonabant and 14h and suggests that Ser383 can H-bond to the nitrogen of the pyridine ring of 14h.…”