Fig. 3.

SR-17018 and SR-14968 display noncompetitive interactions at MOR. (A–C) Competition curves in the ³⁵S-GTPγS binding assay on untreated MOR–CHO cell membranes are presented using increasing concentrations of naloxone in the presence of (A) DAMGO, (B) SR-17018, and (C) SR-14968 concentration response curves. Linear regression Schild analyses demonstrating a linear shift in the potency as a function of antagonist concentration are shown (n = 3). A decrease in the maximum of SR-14968 in the presence of 10 µM Naloxone is indicative of a noncompetitive interaction; the allosteric operational parameter αβ is calculated as 0.0029. (D–F) Radioligand competition studies using (D) ³H-DAMGO, n = 3, (E) ³H-Diprenorphine, n = 4 to 8, and (F) ³H-Naloxone, n = 3, and the indicated competing compounds. The ³H-naloxone competition produced by 1 µM SR-14968 (dashed line with SEM in F) can be reversed by SR-17018 (red triangles); the individual data points are shown for 10 µM SR-17018 (**P < 0.01, paired Student’s t test). See Table 3 for parameters and n values.