Yingxian Xiao

Associate Professor of Pharmacology
Ph.D., Molecular Biology
University of Maryland, 1994
(202) 687-1242
yxiao02@georgetown.edu

Neuronal nicotinic acetylcholine receptors (nAChR) are acetylcholine-gated cation channels that are widely distributed in the central and peripheral nervous systems. The nAChR is found postsynaptically at synapses, where they may mediate signal transduction between neurons. In addition, these receptors are located at presynaptic, perisynaptic and extrasynaptic sites where they may affect signal transduction processes of other neurotransmitters. The nAChRs are likely involved in neuronal development, plasticity, and other physiological roles that are just being revealed. These receptors have also been implicated in diseases such as epilepsy, Alzeimer¡¯s disease, Parkinson¡¯s disease and schizophrenia. The interaction of nAChRs with nicotine is the key step in the process that leads to nicotine addiction.

Each of the nAChRs is thought to be formed from five subunits. Eleven different subunit genes have been identified in vertebrate neuronal tissue, which allows for the possibility of multiple nAChR subtypes. We have expressed the different nAChR subtypes in HEK 293 cells. The stable clonal cell lines generated from the heterologous expression provide cell models for each of the nAChR subtypes. We are using these cell lines to study the molecular biological, pharmacological, functional and pathological characteristics of nAChR subtypes.

Selected Publications:

• Forcelli PA, Turner JR, Lee BG, Olson TT, Xie T, Xiao Y, Blendy JA, Kellar KJ. Anxiolytic- and antidepressant-like effects of the methadone metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP). Neuropharmacology. 101, 46-56, 2015. 
• Tuan EW, Horti AG, Olson TT, Gao Y, Stockmeier CA, Al-Muhtasib N, Bowman Dalley C, Lewin AE, Wolfe BB, Sahibzada N, Xiao Y, Kellar KJ. AT-1001 Is a Partial Agonist with High Affinity and Selectivity at Human and Rat α3β4 Nicotinic Cholinergic Receptors. Mol Pharmacol. 88(4), 640-649, 2015. 
• Beinat C, Reekie T, Banister SD, O’Brien-Brown J, Xie T, Olson TT, Xiao Y, Harvey A, O’Connor S, Coles C, Grishin A, Kolesik P, Tsanaktsidis J, Kassiou M. Structure–activity relationship studies of SEN12333 analogues: Determination of the optimal requirements for binding affinities at α7 nAChRs through incorporation of known structural motifs. 95, 277-301, 2015. 
• Beinat C, Reekie T, Hibbs D, Xie T, Olson TT, Xiao Y, Harvey A, O’Connor S, Coles C, Tsanaktsidis J, Kassiou M. Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333. 84, 200-205, 2014. 
• Liu Y, Paige M, Olson TT, Al-Muhtasib N, Xie T, Hou S, White MP, Cordova A, Guo JL, Kellar KJ,Xiao Y, Brown ML. Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A. Bioorg Med Chem Lett. 24(13), 2954-2956, 2014. 
• Hussmann GP, Dedominicis KE, Turner JR, Yasuda RP, Klehm J, Forcelli PA, Xiao Y, Richardson JR, Sahibzada N, Wolfe BB, Lindstrom J, Blendy JA, Kellar KJ.: Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain. .   J Neurochem. 2014 May;129(4):721-31
• Yenugonda VM, Xiao Y, Levin ED, Rezvani AH, Tran T, Al-Muhtasib N, Sahibzada N, Xie T, Wells C, Slade S, Johnson JE, Dakshanamurthy S, Kong HS, Tomita Y, Liu Y, Paige M, Kellar KJ, Brown ML.: Design, synthesis and discovery of picomolar selective α4β2 nicotinic acetylcholine receptor ligands. .   J Med Chem. 2013 Nov 14;56(21):8404-21
• Levin ED, Sexton HG, Gordon K, Gordon CJ, Xiao Y, Kellar KJ, Yenugonda VM, Liu Y, White MP, Paige M, Brown ML, Rezvani AH.: Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor β2-/- and α7-/- mice. .   Eur J Pharmacol. 2013 Oct 15;718(1-3):167-72
• Liu Y, Richardson J, Tran T, Al-Muhtasib N, Xie T, Yenugonda VM, Sexton HG, Rezvani AH, Levin ED, Sahibzada N, Kellar KJ, Brown ML, Xiao Y, Paige M.: Chemistry and pharmacological studies of 3-alkoxy-2,5-disubstituted-pyridinyl compounds as novel selective a4ß2 nicotinic acetylcholine receptor ligands that reduce alcohol intake in rats. .   J Med Chem. Epub, Apr, 2013
• Rezvani AH, Cauley M, Xiao Y, Kellar KJ, Levin ED Effects of chronic sazetidine-A, a selective alpha4beta2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically-induced impaired attention in rats..    Psychopharmacol 226:35-43, 2013
• Hussmann GP, TurnerJR, Lomazzo E, Venkatesh R, Cousins V, Xiao Y, Yasuda RP, Wolfe BB, Perry DC, Rezvani AH, Levin ED, Blendy JA, Kellar KJ: Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain.   J Pharmacol Exp Ther Aug 16 Epub ahead of print, 2012
• Rezvani AH, Timofeeva O, Sexton HG, Decuir D, Xiao Y, Kellar KJ, Levin ED: Effects of sazetidine-A, a selective alpha4beta2* nicotinic receptor desensitizing agent, on body temperature regulation in mice and rats. Eur. J. Pharmacol. Feb 24 Epub ahead of print, 2012
• Johnson JE, Slade S, Wells C, Petro A, Sexton H, Rezvani AH, Brown ML, Paige MA, McDowell BE, Xiao Y, Kellar KJ, Levin ED: Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats Psychopharmacology Feb 2 Epub ahead of print
• Turner JR Ortinski PI, Sherrard RM, Kellar KJ Cerebellar nicotinic cholinergic receptors are intrinsic to the cerebellum: Implications for diverse functional roles. Cerebellum 10:748-757, 2011
• Hussmann GP, Yasuda RP, Wolfe BB, Xiao, Y, Kellar KJ Endogenously expressed muscarinic receptors in HEK293 cells augment up-regulation of stably expressed alpha4-beta2 nicotinic receptors. J Biol. Chem. 286:39726, 2011
• Levin ED, Rezvani AH, Xiao Y, Slade S, Cauley M, Wells C, Hampton D, Petro A, Rose JE, Brown ML, Paige MA, McDowell BE, Kellar KJ: Sazetidine-A, a Selective {alpha}4{beta}2 Nicotinic Receptor Desensitizing Agent and Partial Agonist, Reduces Nicotine Self-Administration in Rats. J Pharmacol Exp Ther. 332:933-939, 2010
• Hone AJ, Whiteaker P, Christensen S, Xiao Y, Meyer EL, McIntosh JM: A novel fluorescent alpha-conotoxin for the study of alpha7 nicotinic acetylcholine receptors. J Neurochem. 111:80-9, 2009
• Xiao Y, Abdrakhmanova GR, Baydyuk M, Hernandez S, Kellar KJ: Rat neuronal nicotinic acetylcholine receptors containing alpha7 subunit: pharmacological properties of ligand binding and function. Acta Pharmacol Sin. 30:842-50, 2009
• Valette H, Xiao Y, Peyronneau MA, Damont A, Kozikowski AP, Wei ZL, Kassiou M, Kellar KJ, Dolle F, Bottlaender M: 18F-ZW-104: a new radioligand for imaging neuronal nicotinic acetylcholine receptors–in vitro binding properties and PET studies in baboons. J Nucl Med. 50:1349-55, 2009
• Gao Y, Ravert HT, Kuwabara H, Xiao Y, Endres CJ, Hilton J, Holt DP, Kumar A, Alexander M, Wong DF, Dannals RF, Horti AG: Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of alpha4beta2 nicotinic acetylcholine receptors (alpha4beta2-nAChRs) in the brain with positron emission tomography. Bioorg Med Chem. 17:4367-77, 2009
• Cucchiaro G, Xiao Y, Gonzalez-Sulser A, Kellar KJ: Analgesic effects of Sazetidine-A, a new nicotinic cholinergic drug. Anesthesiology. 109:512-9, 2008
• Gao Y, Kuwabara H, Spivak CE, Xiao Y, Kellar K, Ravert HT, Kumar A, Alexander M, Hilton J, Wong DF, Dannals RF, Horti AG: Discovery of (-)-7-methyl-2-exo-[3′-(6-[18F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (alpha4beta2-nAChR) with optimal positron emission tomography imaging properties. J Med Chem. 51:4751-64, 2008
• Chen J, Higby R, Tian D, Tan D, Johnson MD, Xiao Y, Kellar KJ, Feng S, Shields PG: Toxicological analysis of low-nicotine and nicotine-free cigarettes. Toxicology. 249:194-203, 2008
• Moaddel R, Oliveira RV, Kimura T, Hyppolite P, Juhaszova M, Xiao Y, Kellar KJ, Bernier M, Wainer IW: Initial synthesis and characterization of an alpha7 nicotinic receptor cellular membrane affinity chromatography column: effect of receptor subtype and cell type. Anal Chem. 80:48-54, 2008
• Kozikowski AP, Chellappan SK, Xiao Y, Bajjuri KM, Yuan H, Kellar KJ, Petukhov PA. Chemical medicine: novel 10-substituted cytisine derivatives with increased selectivity for alpha4beta2 nicotinic acetylcholine receptors. ChemMedChem. 2:1157-1161, 2007
• Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP: Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity. J Med Chem. 49:2673-6, 2006
• Ohtani M, Oka T, Badyuk M, Xiao Y, Kellar KJ, Daly JW: Mouse beta-TC6 insulinoma cells: high expression of functional alpha3beta4 nicotinic receptors mediating membrane potential, intracellular calcium, and insulin release. Mol Pharmacol. 69:899-907, 2006
• Xiao Y, Fan H, Musachio JL, Wei ZL, Chellappan SK, Kozikowski AP, Kellar KJ: Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them. Mol Pharmacol. 70:1454-60, 2006
• Huang Y, Zhu Z, Xiao Y, Laruelle M: Epibatidine analogues as selective ligands for the alpha(x)beta2-containing subtypes of nicotinic acetylcholine receptors. Bioorg Med Chem Lett. 15:4385-8, 2005
• Marritt AM, Cox BC, Yasuda RP, McIntosh JM, Xiao Y, Wolfe BB, Kellar KJ: Nicotinic cholinergic receptors in the rat retina: simple and mixed heteromeric subtypes. Mol Pharmacol. 68:1656-68, 2005
• Wei ZL, Xiao Y, Yuan H, Baydyuk M, Petukhov PA, Musachio JL, Kellar KJ, Kozikowski APNovel pyridyl ring C5 substituted analogues of epibatidine and 3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine (A-84543) as highly selective agents for neuronal nicotinic acetylcholine receptors containing beta2 subunits. J Med Chem. 48:1721-4, 2005

• Wei ZL, Xiao Y, Kellar KJ, Kozikowski AP: Synthesis and pharmacological characterization of bivalent ligands of epibatidine at neuronal nicotinic acetylcholine receptors. Bioorg Med Chem Lett. 14:1855-8, 2004, 2004
• Hernandez SC, Vicini S, Xiao Y, Davila-Garcia MI, Yasuda RP, Wolfe BB, Kellar KJ: The nicotinic receptor in the rat pineal gland is an alpha3beta4 subtype. Mol Pharmacol. 66:978-87, 2004
• Xiao Y, Baydyuk M, Wang HP, Davis HE, Kellar KJ: Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells. Bioorg Med Chem Lett. 14:1845-8, 2004
• Xiao Y, Kellar KJ: The comparative pharmacology and up-regulation of rat neuronal nicotinic receptor subtype binding sites stably expressed in transfected mammalian cells. J Pharmacol Exp Ther. 310:98-107, 2004
• Wei ZL, Xiao Y, George C, Kellar KJ, Kozikowski AP: Functionalization of the alicyclic skeleton of epibatidine: synthesis and nicotinic acetylcholine receptor binding affinities of epibatidine analogues. Org Biomol Chem. 1:3878-81, 2003
• Avila AM, Davila-Garcia MI, Ascarrunz VS, Xiao Y, Kellar KJ. Differential regulation of nicotinic acetylcholine receptors in PC12 cells by nicotine and nerve growth factor. Mol Pharmacol. 64:974-86, 2003
• Wei ZL, Petukhov PA, Xiao Y, Tückmantel W, George C, Kellar KJ, Kozikowski AP: Synthesis, nicotinic acetylcholine receptor binding affinities, and molecular modeling of constrained epibatidine analogues. J Med Chem. 46:921-4, 2003
• Fitch RW, Xiao Y, Kellar KJ, Daly JW. Membrane potential fluorescence: a rapid and highly sensitive assay for nicotinic receptor channel function. Proc Natl Acad Sci. 100:4909-14, 2003
• Abdrakhmanova G, Dorfman J, Xiao Y, Morad M: Protons enhance the gating kinetics of the alpha3/beta4 neuronal nicotinic acetylcholine receptor by increasing its apparent affinity to agonists. Mol Pharmacol. 61:369-78, 2002
• Perry DC, Xiao Y, Nguyen HN, Musachio JL, Davila-Garcia MI, Kellar KJ. Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 subtypes in rat tissues by autoradiography. J Neurochem. 82:468-81, 2002
• Fan H, Scheffel UA, Rauseo P, Xiao Y, Dogan AS, Yokoi F, Hilton J, Kellar KJ, Wong DF, Musachio JL: [125/123I] 5-Iodo-3-pyridyl ethers. syntheses and binding to neuronal nicotinic acetylcholine receptors. Nucl Med Biol. 28:911-21, 2001
• Xiao Y, Smith RD, Caruso FS, Kellar KJ: Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs. J Pharmacol Exp Ther. 299:366-71, 2001
• Meyer EL, Xiao Y, Kellar KJ: Agonist regulation of rat alpha 3 beta 4 nicotinic acetylcholine receptors stably expressed in human embryonic kidney 293 cells. Mol Pharmacol. 60(3):568-76, 2001
• Yeh JJ, Yasuda RP, Davila-Garcia MI, Xiao Y, Ebert S, Gupta T, Kellar KJ, Wolfe BB: Neuronal nicotinic acetylcholine receptor alpha3 subunit protein in rat brain and sympathetic ganglion measured using a subunit-specific antibody: regional and ontogenic expression. J Neurochem. 77(1):336-46, 2001
• Hernandez SC, Bertolino M, Xiao Y, Pringle KE, Caruso FS, Kellar KJ: Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors. J Pharmacol Exp Ther. 293:962-7, 2000
• Zhang J, Xiao Y, Abdrakhmanova G, Wang W, Cleemann L, Kellar KJ, Morad M: Activation and Ca2+ permeation of stably transfected alpha3/beta4 neuronal nicotinic acetylcholine receptor. Mol Pharmacol. 55:970-81, 1999
• Wainer IW, Zhang Y, Xiao Y, Kellar KJ: Liquid chromatographic studies with immobilized neuronal nicotinic acetylcholine receptor stationary phases: effects of receptor subtypes, pH and ionic strength on drug-receptor interactions. J Chromatogr B Biomed Sci Appl. 724:65-72, 1999
• Kellar KJ, Davila-Garcia MI, Xiao Y: Pharmacology of neuronal nicotinic acetylcholine recceptors: effects of acute and chronic nicotine. Nicotine Tob Res. 1 Suppl 2:S117-20, 1999
• Zhang Y, Xiao Y, Kellar KJ, Wainer IW: Immobilized nicotinic receptor stationary phase for on-line liquid chromatographic determination of drug-receptor affinities. Anal Biochem. 264:22-5, 1998
• Xiao Y, Meyer EL, Thompson JM, Surin A, Wroblewski J, Kellar KJ: Rat alpha3/beta4 subtype of neuronal nicotinic acetylcholine receptor stably expressed in a transfected cell line: pharmacology of ligand binding and function. Mol Pharmacol. 54:322-33, 1998
• Davila-Garcia MI, Musachio JL, Perry DC, Xiao Y, Horti A, London ED, Dannals RF, Kellar KJ: [125I]IPH, an epibatidine analog, binds with high affinity to neuronal nicotinic cholinergic receptors. J Pharmacol Exp Ther. 282:445-51, 1997

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