Fig. 2: Structure-activity relationships and optimization of ‘51486 to ‘1350 and ‘4936.
From: Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects
a Pharmacophore model based on the structure-activity relationships discovered via analoging ‘51486. b 2D structures and properties of the docking hit ‘51486 and most potent analogs. c Docking predicted pose of ‘51486 (teal) and ‘60154 (purple). d Docking predicted pose of ‘1350 (maroon) and ‘4936 (navy). e–g Binding affinity to rodent CB1R (rCB1) or functional cAMP inhibition to human CB1R (hCB1) by the ‘51486 analog series compared to CP-55,940. One-way ANOVA statistical significance of individual pKi (e; F (6, 13) = 152.2, P < 0.0001) or pEC50 (f; F (3, 19) = 154.9, P < 0.0001). Comparisons to CP-55,940 after correction with Dunnett’s test of multiple hypotheses are depicted in the table. pKi: CP-55,940 vs. ‘51486 and ‘60154: P < 0.0001; vs. ‘1350: P = 0.007; vs. ‘4936: P = 0.04. pEC50: CP-55,940 vs. ‘60154: P < 0.0001; vs. ‘1350: P = 0.0001; vs. ‘4936: P = 0.96. Data in e & f represent mean ± SEM from two or three independent experiments run in technical triplicate, respectively. ns = not significant, *P < 0.05, **P < 0.01, ****P < 0.001.
