Mechanism-Based Discovery of Small Molecules that Prevent Noncompetitive Inhibition by Cocaine and MK-801 Mediated by Two Different Sites on the Nicotinic Acetylcholine Receptor†

The nicotinic acetylcholine receptor (nAChR) belongs to a group of five structurally related membrane proteins that play a major role in the communication between ∼1012 cells of the mammalian nervous system. The receptor is inhibited by both abused drugs and therapeutic agents. During the past two decades, many attempts have been made to find compounds that prevent cocaine inhibition of this protein. The use of newly developed transient kinetic techniques in investigations of the inhibition of the receptor by cocaine and MK-801 led to an inhibition mechanism not previously proposed. It was observed that the receptor contains two inhibitory sites:  one that equilibrates with the tested noncompetitive inhibitors within ∼50 ms, and a second site that equilibrates with inhibitors within ∼1 s. The mechanism of inhibition of the rapidly equilibrating inhibitory site has been investigated, and based on that mechanism, the first evidence that small organic molecules exist that prevent inhibition of the rapidly eq...