Document Type

Article

Original Publication Date

2016

Journal/Book/Conference Title

ACS Chemical Neuroscience

Volume

7

Issue

11

First Page

1565

Last Page

1574

DOI of Original Publication

10.1021/acschemneuro.6b00196

Comments

Originally published at http://doi.org/10.1021/acschemneuro.6b00196

Date of Submission

January 2017

Abstract

Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT3) receptor ligands resulted in a broad spectrum of functionally-active ligands from antagonist to superagonist. For example, (i) introduction of an additional Cl-substituent(s) to our lead full agonist N-(3-chlorophenyl)guanidine (mCPG, 2; efficacy % = 106) yielded superagonists 7-9 (efficacy % = 186, 139, and 129, respectively), (ii) a positional isomer of 2, p-Cl analog 11, displayed partial agonist actions (efficacy % = 12), and (iii) replacing the halogen atom at the meta or para position with an electron donating OCH3 group or a stronger electron withdrawing (i.e., CF3) group resulted in antagonists 13-16. We posit based on combined mutagenesis, crystallographic, and computational analyses that for the 5-HT3 receptor, the arylguanidines that are better able to simultaneously engage the primary and complementary subunits, thus keeping them in close proximity, have greater agonist character while those that are deficient in this ability are antagonists.

Rights

Copyright © 2016 American Chemical Society

Is Part Of

VCU Neurology Publications

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