title: Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms.
abstract: This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca(2+) influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6') and valine (position 13') rings that overlaps the imipramine binding site.
authors: Department of Medical Education, California Northstate University College of Medicine, Elk Grove, CA 95757, USA. Electronic address: hugo.arias@cnucom.org.
authors: Hugo R
authors: HR
authors: Arias
authors: Jhon J
authors: JJ
authors: López
authors: Dominik
authors: D
authors: Feuerbach
authors: Angélica
authors: A
authors: Fierro
authors: Marcelo O
authors: MO
authors: Ortells
authors: Edwin G
authors: EG
authors: Pérez
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008024:Ligands; D062105:Molecular Docking Simulation; D011812:Quinuclidines / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D007473:Ion Channels; D008024:Ligands; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D002118:Calcium
keywords: ACh; CCh; Competitive antagonists; EC(50); Hill coefficient; IC(50); K(i); Nicotinic acetylcholine receptors; Noncompetitive antagonists; Quinuclidines; RMSD; RT; Structure–activity relationship; [(3)H]MLA; [(3)H]methyllycaconitine; acetylcholine; agonist concentration that produces 50% AChR activation; carbamylcholine; inhibition constant; ligand concentration that produces 50% inhibition (of binding or of agonist activation); n(H); nAChR; nicotinic acetylcholine receptor; room temperature; root mean square deviation