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Structure‐Activity Considerations for Heteroaromatic nortropeines and N‐methyltropeines with Nicotinic Acetylcholine Receptor (nAChR) Subtypes and a Serotonin Receptor (5HT3A)
Author(s) -
Serrano Aracely,
Nemecz Ákos,
Gomez Kimberly,
Maksay Gábor,
Yamahuchi John George,
Taylor Palmer
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb550
Subject(s) - chemistry , stereochemistry , nicotinic acetylcholine receptor , nicotinic agonist , ligand gated ion channel , acetylcholine receptor , receptor , ion channel , biochemistry
A series of heteroaromatic tropeines have been studied as potentiators of the glycine receptor. We show here a range of potencies for these compounds as agonists and antagonists on excitatory pentameric ligand‐gated ion channels (pLGIC), such as the nAChR and 5HT3A receptor. We have analyzed the interactions of 19 heteroaromatic tropeines, including nor and N‐methyltropeine congeners, with the soluble acetylcholine binding protein (AChBP), a structural extracellulardomain surrogate of pLGICs, and quantified their activities at hα7 and α4β2‐nAChRs and the mouse 5HT3A receptor. Pharmacological studies on hα7‐nAChR reveal the more potent compounds to be agonists with EC50 values ranging between 28–200 nM. By contrast, some of the set of compounds showed antagonist activity on α4β2‐nAChR and 5HT3A receptors with a range of selectivity. In turn, we have compared their pharmacologic spectra of activities with a previously studied series of related azabicyclic heterocycles linked to triazoles by click‐chemistry. Analysis of binding selectivity and pharmacologic activity, when combined with structural analysis, achieved through X‐ray crystallographic structures of tropine‐AChBP complexes, has enabled us to define the molecular determinants of selectivity for the tropine, acylester and linked triazole moieties in this series of pLGIC ligands. Supported by USPHS grant GM18360 and México CONCyT‐18622.