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N1H- and N1-Substituted Phenylguanidines as α7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure-Activity Relationship Studies

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We previously reported that N-(3-chlorophenyl)guanidine (1) represents a novel α7 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 α7 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., <10-fold) effect on potency, and the presence of an N1-isopropyl substituent was tolerated. Here, we report the first SAR investigation of this novel α7 nAChR antagonist chemotype.

Original languageEnglish
JournalACS Chemical Neuroscience
Volume12
Issue number12
Pages (from-to)2194-2201
Number of pages8
ISSN1948-7193
DOIs
Publication statusPublished - 16 Jun 2021

    Research areas

  • Acetylcholine, Animals, Guanidines, Humans, Nicotinic Antagonists/pharmacology, Oocytes/metabolism, Receptors, Nicotinic/metabolism, Structure-Activity Relationship, Xenopus laevis, alpha7 Nicotinic Acetylcholine Receptor, SAR, antagonist, electrophysiology, α7 nAChR, phenylguanidines

ID: 67558895