Abstract
meta-Chlorophenylguanidine (1) is a non-competitive α7 nicotinic acetylcholine receptor (nAChR) antagonist. Here we examined the hydrogen bond donor role of the anilinic N1–H on the inhibitory effect of 1 by preparing its N1–CH3 counterpart 2. Analog 2 was found to be at least as potent as 1 as a non-competitive α7 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 hα7 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 α7 nAChRs. These differences in the binding orientations minimized the importance of an anilinic NH function for the antagonist activity at nACh receptors.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
