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ACS Chem Neurosci. 2016 Nov 16;7(11):1565-1574. Epub 2016 Sep 6.

Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT3) Subunit A Receptors.

Author information

1
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
2
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of Sciences , Philadelphia, Pennsylvania 19104, United States.
3
Department of Biochemistry and Molecular Biology Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.

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.

KEYWORDS:

3D-graphic models; 5-HT3A receptors; Arylguanidines; SAR; binding affinities; functional activities; site-directed mutagenesis

PMID:
27533595
DOI:
10.1021/acschemneuro.6b00196
[Indexed for MEDLINE]

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