N1H- and N1-Substituted Phenylguanidines as alpha 7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure-Activity Relationship Studies

Osama Alwassil, Shailesh Khatri, Marvin K. Schulte, Sanjay S. Aripaka, Jens D. Mikkelsen, Malgorzata Dukat*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

2 Citations (Scopus)

Abstract

We previously reported that N-(3-chlorophenyl)guanidine (1) represents a novel alpha 7 nicotinic ACh (nACh) receptor antagonist chemotype. In the present study, a small series of compounds was synthesized with the intent to investigate the structure-activity relationship (SAR). Preliminary data suggested that the N-methyl analog of 1, 2, was several times more potent. Therefore, the chloro group at the aryl 3-position of 1 and its N1-methyl counterpart 2 were replaced with a number of substituents considering the electronic, lipophilic, and steric nature of the substituents. The potencies of the compounds to inhibit acetylcholine (ACh)-induced responses were obtained in Xenopus laevis oocytes expressing human alpha 7 nicotinic ACh receptors (nAChRs) using a two-electrode voltage-clamp assay. We found that the nature of the 3-position substituents had relatively little (i.e.,

Original languageEnglish
JournalACS Chemical Neuroscience
Volume12
Issue number12
Pages (from-to)2194-2201
Number of pages8
ISSN1948-7193
DOIs
Publication statusPublished - 2021

Keywords

  • alpha 7 nAChR
  • SAR
  • electrophysiology
  • antagonist
  • phenylguanidines
  • ALLOSTERIC MODULATORS
  • ARYLGUANIDINES
  • BINDING

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