title: Pyrilamine inhibits nicotine-induced catecholamine secretion.
abstract: Function of nicotine, which induces activation of all parts of the body including our brain, has been receiving much attention for a long period of time and also been actively studied by researchers for its pharmacological actions in the central nervous system. The modulation of nicotine concentration and the inhibition of nicotine binding on target receptors in the brain are the key factors for smoking addiction therapy. In previous studies showed that influx of nicotine at the blood-brain barrier was through the pyrilamine-sensitive organic cation transporters. But the direct interacting mechanism of pyrilamine on the nicotine binding target receptors has not yet been clarified. The aim of the present study is to investigate the direct binding mechanisms of a pyrilamine on the nicotinic acetylcholine receptors (nAChRs). We found that pyrilamine shares the same ligand binding pocket of nicotine (NCT) on nAChRs but interacts with more amino acid residues than NCT does. The extended part of pyrilamine interacts with additional residues in the ligand binding pocket of nAChRs which are located nearby the entrance of the binding pocket. The catecholamine (CA) secretion induced by nAChR agonist (NCT') was significantly inhibited by the pyrilamine pretreatment. Real time carbon-fiber amperometry confirmed the inhibition of the NCT'-induced exocytosis by pyrilamine in a single cell level. We also found that pyrilamine inhibited the NCT'-induced [Ca(2+)]i. In contrast, pyrilamine did not affect the increase in calcium induced by high K(+). Overall, these data suggest that pyrilamine directly docks into the ligand binding site of nAChRs and specifically inhibits the nAChR-mediated effects thereby causing inhibition of CA secretion. Therefore, pyrilamine may play an important role to explore new treatments to aid smoking cessation.
authors.affiliation: Division of Molecular and Life Science, System Bio-Dynamics, POSTECH, Pohang, Republic of Korea; Department of Biomedical Laboratory Science, Gimcheon University, Gimcheon 740-704, Republic of Korea; Division of Molecular and Life Science, POSTECH, Pohang, Republic of Korea; Laboratory of Microvascular Circulation Research, NEURONEX Inc., Goryung, Republic of Korea. Electronic address: kim.dongchan@gmail.com.
authors.forename: Dong-Chan
authors.initials: DC
authors.lastname: Kim
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea.
authors.forename: So Jeong
authors.initials: SJ
authors.lastname: Yun
authors.affiliation: Division of Molecular and Life Science, System Bio-Dynamics, POSTECH, Pohang, Republic of Korea.
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Park
authors.affiliation: Division of Molecular and Life Science, System Bio-Dynamics, POSTECH, Pohang, Republic of Korea.
authors.forename: Dong-Jae
authors.initials: DJ
authors.lastname: Jun
authors.affiliation: Technical & Industrial Division, Athens Technical College, 800 US Highway 29 North, Athens, GA 30601-1500, USA.
authors.forename: Dongjin
authors.initials: D
authors.lastname: Kim
authors.affiliation: Center for Superfunctional Materials, Department of Chemistry, POSTECH, Pohang, Republic of Korea.
authors.forename: N
authors.initials: N
authors.lastname: Jiten Singh
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea; Division of ITCE Engineering, POSTECH, Pohang, Republic of Korea; Division of Molecular and Life Science, POSTECH, Pohang, Republic of Korea. Electronic address: sukim@postech.ac.kr.
authors.forename: Sanguk
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Molecular and Life Science, System Bio-Dynamics, POSTECH, Pohang, Republic of Korea; Division of Molecular and Life Science, POSTECH, Pohang, Republic of Korea. Electronic address: ktk@postech.ac.kr.
authors.forename: Kyong-Tai
authors.initials: KT
authors.lastname: Kim
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D005089:Exocytosis / Q000502:physiology; D062105:Molecular Docking Simulation; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011738:Pyrilamine / Q000378:metabolism / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism / Q000502:physiology
chemical_list: D002395:Catecholamines; D011978:Receptors, Nicotinic; D009538:Nicotine; D011738:Pyrilamine
keywords: Nicotine; Nicotinic acetylcholine receptor; Pyrilamine; Smoking cessation