Figure 4.

A minimal mechanism of inhibition for BDZ-f. The upper row shows the channel-opening reaction of the AMPA receptor. A represents the active, unliganded form of the receptor, L the ligand (glutamate), AL and AL₂ the ligand-bound closed-channel forms, $\overline{A{L}_2}$ the open-channel form or the state of the receptor (all the species with a bar sign refer to open-channel state), k_op the channel-opening rate constant, and k_cl the channel-closing rate constant. For simplicity and without contrary evidence, it is assumed that glutamate binds to the two steps with equal affinity, represented by the same intrinsic equilibrium dissociation constant, K₁. The initial binding of BDZ-f to the receptor is assumed to form a loosely bound, partially conducting intermediate (e.g., ${\overline{IAL}}_2^{*}$) in both the closed-channel and open-channel states of the receptor (middle row). In the second step (from the middle to the lower row), the receptor:inhibitor intermediate rapidly isomerizes into a more tightly bound complex $(\overline{IA{L}_2})$, and such a complex is no longer capable of conducting ions. The inhibition constants pertinent to various steps in this mechanistic scheme are shown in Table 1. K_I represents the overall inhibition constant associated with the closed-channel state of the receptor (i.e., the values from Column 5 in Table 1), K̅_I, the overall inhibition constant associated with open-channel state (i.e., the values from Column 6 in Table 1), I, the inhibitor, k_op' the channel-opening rate constant of the inhibited AMPA receptor, k_cl' the channel-closing rate constant of the inhibited AMPA receptor. In addition, the values for $K_I^{*}$ and ${\overline{K}}_I^{*}$ for step 1 can be found from Columns 1 and 2 in Table 1.