Table 1.
The key binding interactions of DH-based analogs in GluK1–LBC coupled to binding affinity, activation, and desensitization.
| Ligand | Ki (nM)a | Activationa | Desensitizationa | C8b | C9b | H1c | H2d | H3e |
|---|---|---|---|---|---|---|---|---|
| DH | 0.5 | ++ | ++ | |||||
| neoDH | 7.7 | ++ | ++ | Y | X | + | + | X |
| 8-deoxy-neoDH | 1.5 | ++ | ++ | − | X | + | + | X/wX |
| 8-epi-neoDH | 34 | ++ | ++ | R | X | + | + | wX |
| 9-F-8-epi-neoDH | 28 | ++ | ++ | R | F | + | + | wX |
| 9-deoxy-neoDH | 169 | + | + | Y | − | + | − | − |
| 9-epi-neoDH | 292 | + | + | Y | R | + | + | − |
| 8,9-epi-neoDH | 48,000 | − | − | R | R | − | + | − |
| 4-epi-neoDH | 559 | + | ++ | − | − | − | + | − |
| 2,4-epi-neoDH | 2400 | − | ++ | − | − | − | − | − |
| MSVIII-19 | 128 | − | + | − | − | + | +/− | − |
Experimental data from Lash et al. (2008), except for DH from Sakai et al. (2001). Activation refers to the strength of the receptor activation, and desensitization refers to the length of the receptor inaction after ligand binding.
The C8 and C9 groups of DH (X: C9 positioned hydroxyl with the same stereochemistry as DH, Y: hydroxyl with the same stereochemistry as C8 methylamine group of DH, R: hydroxyl with reversed stereochemistry from DH, F = hydroxyl substituted with fluorine) compared.
H1: Hydrogen-bonds connect the D1 and D2 lobes between Gly490O and Asp687N (from MD simulations).
H2: Hydrogen-bonds connect the D1 and D2 lobes between the side chains of Glu441 and Ser721 (from MD simulations).
H3: The Glu738N is hydrogen bonded to the ligand’s C9 hydroxyl (X: direct hydrogen bond, wX: connected via mediating water molecule or molecules) (from MD simulations).