Abstract
meta-Chlorophenylguanidine (1) is a non-competitive alpha 7 nicotinic acetylcholine receptor (nAChR) antagonist. Here we examined the hydrogen bond donor role of the anilinic N-1-H on the inhibitory effect of 1 by preparing its N-1-CH3 counterpart 2. Analog 2 was found to be at least as potent as 1 as a non-competitive alpha 7 nAChR antagonist in a patch-clamp assay.
To establish a structural basis for the mode of interaction of guanidines 1 and 2, we generated 100 homology models of the h alpha 7 nAChR. This was followed by Connolly surface (SYBYL-X2.1) and blind docking (AutoDock 4.1) studies to identify eight possible binding pockets, two of which were supported by empirical data and employed in our docking studies. The optimized model-ligand complexes were analyzed using a Hydropathic INTeractions (HINT) analysis in order to compare and contrast different binding pockets and modes. We identified a potential allosteric binding site and distinct rotameric binding modes for 1 and 2 at alpha 7 nAChRs. These differences in the binding orientations minimized the importance of an anilinic NH function for the antagonist activity at nACh receptors.