Structure‐activity Relationships of Bicyclic Amine Heterocycles with α7 Nicotinic Acetylcholine Receptors (nAChR) and Related Ligand‐gated Ion Channels

• Published in: The FASEB journal 2013-04, Vol.27 (S1)
• Main Authors: Gomez, Kimberly, Yamauchi, John G., Nemecz, Akos, Ho, Kwok‐Yiu, Talley, Todd T., Taylor, Palmer
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.27.1_supplement.lb554

Abstract only nAChRs are pentameric ligand‐gated ion channels (pLGIC) of the Cys‐loop receptor family located in the central and peripheral NS. The two most abundant subtypes in brain, α7 and α4β2, are targeted for development of selective ligands for managing Alzheimer's disease, schizophrenia, Parkinson's disease and tobacco cessation. Responses for human α7 and α4β2 nAChRs, as well as mouse 5‐HT 3A pLGICs, were characterized by fluorescent functional assay using a genetically encoded indicator of Ca 2+ flux through pLGICs. Pharmacological tests with α7 nAChRs in the presence of PNU‐120596 identified 19 of 21 compounds as agonists with sub‐μM IC50's. None were found to be antagonists. Two of 21 compounds were agonists for α4β2 nAChRs, whereas 6 were found to be antagonists. None of the compounds displayed agonist activity when tested with 5‐HT 3A receptors, and 4 were found to be antagonists. The α7 nAChR agonists were characterized by concentration‐response curves with EC 50 values ranging from 1nM to 30 nM. Competitive KA values for α4β2 nAChRs and 5‐HT 3A receptors were calculated from dose‐response curves and Schild plots. Binding constants of several of these compounds were also determined with the acetylcholine binding protein, since structures of these complexes are amenable to crystallographic analysis and ascertaining binding poses and determinants of selectivity.