Hugo R. Arias, PhD

Hugo R. Arias, PhD


Academic Title
Director, Center for Research in Molecular Pharmacology
Assistant Dean of Research (College of Medicine)
Professor of Pharmacology and Biochemistry (College of Medicine)

Contact Information
Phone: (916) 686-7300; (916) 647-0458 (office)
Email: hugo.arias@cnsu.edu






Research Projects:
Since 1984 Dr. Arias has worked in the field of ligand-gated ion channels, more particularly on nicotinic acetylcholine receptors (AChRs). In the last 10 years, Dr. Arias has focused his attention on the role of AChRs in drug addiction, depression and anxiety, and Alzheimer’s disease and schizophrenia. He is currently developing novel ligands for the treatment of these diseases. He has obtained several intramural and extramural grants. He has amassed a large number of publications in peer-review journals (81), book chapters (15), as well as abstracts and oral presentations, and editorials (3).

Regarding the role of AChRs in nicotine (and drug) addiction, our laboratory is using a variety of approaches at the molecular, neuronal, and whole animal levels. For example, we are studying the pharmacological and structural properties of drugs that are in the market for smoking cessation therapy, as well as drugs that are in clinical stage with demonstrated anti-addictive properties [e.g., 18-methoxycoronaridine (18-MC) and its derivatives], and novel competitive antagonists on different human AChR subtypes. For this part of the project, Ca2+ influx, radioligand binding, molecular modeling, docking, and molecular dynamics approaches are used. The role of the β4 subunit in drug (and nicotine) addiction and in the anti-addictive effects mediated by varenicline and 18-MC are being studied by using the behaviour model “cocaine-induced locomotor sensitization” on β4-/- mutant vs wild-type mice (male vs female).

Regarding the role of AChRs in the pharmacological activity of antidepressants, several molecular, structural, and behaviour approaches are being used. For instance, we are studying the pharmacological properties of structurally and functionally different antidepressants that are in the market for depression therapy, drugs that are in the market for smoking cessation therapy, and drugs that are in pre-clinical and clinical stages, on different human AChR subtypes. Electrophysiology experiments have been very helpful to determine that antidepressants inhibit AChRs by different mechanisms. Additional molecular docking and NMR experiments are helping to localize and characterize the binding sites for drugs with antidepressant activity (luminal and non-luminal). At the neuronal level, the effects of selective α7 AChR agonists and positive allosteric modulators (PAMs), and different antidepressants are being studied by using hippocampal brain slices. At the whole animal level, the antidepressant action of some these compounds is determined by using the behaviour model called “forced swim test”. More specifically, the acute, chronic, and withdrawal activities of these drugs are tested on β4-/- mutant vs wild-type mice (male vs female). Ultimately, these studies will test the hypothesis whether an increased cholinergic activity (or hypersensitivity) over the adrenergic system may result in depression or not.

We are also interested in developing nicotinic ligands that can be used for the treatment of Alzheimer’s disease and schizophrenia. To test the hypothesis that the stimulation of α7 AChRs may delay the irreversible development of the Alzheimer’s disease and schizophrenia, we synthesized and pharmacologically characterized a series of novel PAMs with selectivity for α7 AChRs. Since PAMs do not have intrinsic activity but enhance the activity of agonists, we speculate that the activity of these compounds in the brain of Alzheimer’s disease patients can boost the endogenous activity of the neurotransmitter ACh. In fact, animal behavioural studies demonstrated that these PAMs produce pro-cognitive activity per se, probably enhancing the activity of ACh. At the neuronal level, the effects of selective α7 AChR agonists and PAMs are being studied by using hippocampal brain slices. Additional animal behaviour studies (e.g., water maze) will be conducted to determine the behaviour activity of the most promising compounds in terms of increasing memory/cognition, brain faculties that are decreased in Alzheimer’s disease and schizophrenia patients.

In conclusion, my laboratory has been actively involved in the characterization of several different nicotinic ligands that can be used as lead compounds for the development of therapies for the treatment of drug addiction, depression, anxiety, Alzheimer’s disease, and schizophrenia.

Current Grants: 
SONATA funding, National Science Centre, Poland. Project: Analysis of the structural and functional mechanisms of action of nicotinic receptor modulators. Scientific collaboration with Dr. K. Targowska-Duda, Laboratory of Medicinal Chemistry and Neuroengineering, Department of Chemistry, Medical University of Lublin, Lublin, Poland. March, 2014-February, 2016. Total: 461.950 PLN (~$144,359).

The Åhlen Foundation, Sweden. Project: Experimental strategies for improvement of pharmacological treatment in schizophrenia by selective α7 nicotinic receptor ligands: focus on cognition. Co-PI of an international scientific collaboration with Dr. Marie-Louis Wadenberg, Faculty of Health & Life Sciences, Linnaeus University, Kalmar, Sweden. January, 2015-March 31st, 2016. Total: 100,000 SEK (~$15,000).

Publications (most representatives from the last 3 years): 
Arias, H.R., Fedorov, N.B., Benson, L.C., Lippiello, P., Gatto, G.J., Feuerbach, D., and Ortells, M.O. (2013) Functional and structural interaction of (-)-reboxetine with the human α42 nicotinic acetylcholine receptor. J. Pharmacol. Exp. Ther. 344, 113-123.

Taylor, D.H., Burman, P.N., Hansen, D.M., Wilcox, R.S., Larsen, B.R., Blanchard, J.K., Merrill, C.B., Edwards, J.G., Sudweeks, S.N., Wu, J., Arias, H.R., and Steffensen, S.C. (2013) Nicotine enhances the excitability of gaba neurons in the ventral tegmental area via activation of alpha7 nicotinic receptors on glutamate terminals. Biochem. Pharmacol. S1, 007 (9 pages) (Special issue: Psycho- and Neuropharmacology) (doi:10.4172/2167-0501.S1-007).

Pérez, E.G., Ocampo, C., Feuerbach, D., López, J.J., Morelo, G.L., Tapia, R.A., and Arias, H.R. (2013) Novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodides are competitive antagonists of the human α4β2 and α7 nicotinic acetylcholine receptors. Med. Chem. Commun. 4, 1166-1170.

Arias, H.R., Ortells, M.O., and Feuerbach, D. (2013) (-)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites. Neurochem. Int. 63, 423-431.

Arias, H.R., Targowska-Duda, K.M., Feuerbach, D., and Jozwiak, K. (2013) Mecamylamine inhibits muscle nicotinic acetylcholine receptors by competitive and noncompetitive mechanisms. OA Biochemistry 1, 7 (15 pages). www.oapublishinglondon.com/images/article/pdf/1381010397.pdf

Arias, H.R., López, J.J., Feuerbach, D., Fierro, A., Ortells, M.O., and Pérez, E.G. (2013) Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms. Int. J. Biochem. Cell Biol. 45, 2420-2430.

Targowska-Duda, K.M., Jozwiak, K., and Arias, H.R. (2013) Role of the nicotinic receptor 4 subunit in the antidepressant activity of novel N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine enantiomers. Neurosci. Lett. 553, 186-190.

Radhakrishnan, R., Escobar, L., Santamaría, A., and Arias, H.R. (2013) The β4 nicotinic receptor subunit modulates the chronic antidepressant activity mediated by bupropion. Neurosci. Lett. 555, 68-72.

Arias, H.R., De Rosa, M.J., Bergé, I., Feuerbach, D., and Bouzat, C. (2013) Differential pharmacological activity of JN403 between α7 and muscle nicotinic acetylcholine receptors. Biochemistry 52, 8480-8488.

Arias, H.R., Targowska-Duda, K.M., and Jozwiak, K. (2013) N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine enantiomers interact with the human α42 nicotinic receptor to luminal and non-luminal binding sites. OA Biochemistry 1, 11 (10 pages).

Bondarenko, V., Targowska-Duda, K.M., Jozwiak, K., Tang, P., and Arias, H.R. (2014) Interaction of mecamylamine isomers with the transmembrane domain of the α42 nicotinic receptor. Biochemistry 53, 908-918.

Targowska-Duda, K.M., Feuerbach, D., Biała, G., Jozwiak, K., and Arias, H.R. (2014) Antidepressant activity in mice elicited by 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic receptor. Neurosci. Lett. 569, 126-130.

Vázquez-Gómez, E., Arias, H.R., Feuerbach, D., Miranda-Morales, M., Mihailescu, S., Targowska-Duda, K.M., Jozwiak, K., and García-Colunga, J. (2014) Bupropion-induced inhibition of α7 nicotinic acetylcholine receptors expressed in heterologous cells and neurons from dorsal raphe nucleus and hippocampus. Eur. J. Pharmacol. 740, 103-111.

Arias, H.R., Feuerbach, D., Targowska-Duda, K.M., Kaczor, A.A., Poso, A., and Jozwiak, K. (2015) Pharmacological and molecular studies on the interaction of varenicline with different nicotinic acetylcholine receptors. Potential mechanism underlying partial agonism at human α4β2 and α3β4 subtypes. Biochem. Byophys. Acta - Biomembranes, 1848, 731-741.

Arias, H.R., Targowska-Duda, K.M., and Jozwiak, K. (2015) N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine enantiomers interact with the human α34 nicotinic receptor at luminal and non-luminal binding sites. J. Biochem. Mol. Biol. Res. 1, 19-24.

Arias, H.R., Feuerbach, D., and Ortells, M.O. (2015) Functional and structural interaction of (-)-lobeline with human α4β2 and α4β4 nicotinic acetylcholine receptor subtypes. Int. J. Biochem. Cell Biol. 64, 15-24.

Arias, H.R., Feuerbach, D., Targowska-Duda, K.M., and Jozwiak, K. (2015) Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites. Int. J. Biochem. Cell Biol. 65, 81-90.

Arias, H.R., Targowska-Duda, K.M., Feuerbach, D., and Jozwiak, K. (2015) The antidepressant-like activity of nicotine, but not of 3-furan-2-yl-N-p-tolyl-acrylamide, is regulated by the nicotinic receptor β4 subunit. Neurochem. Int. 87, 110-116.

Möller-Acuña, P., Contreras-Riquelme, J.S., Rojas-Fuentes, C., Nuñez-Vivanco, G., Alzate-Morales, J., Iturriaga-Vásquez, P., Arias, H.R., and Reyes-Parada, M. (2015) Similarities between the binding sites of SB-206553 at serotonin type 2 and α7 acetylcholine nicotinic receptors: Rationale for its polypharmacological profile. PLoS ONE 10(8), e0134444.

Potasiewicz, A., Kos, T., Ravazzini, F., Puja, G., Arias, H.R., Popik, P., and Nikiforuk, A. (2015). Procognitive activity in rats of 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor. Br. J. Pharmacol., doi: 10.1111/bph.13277.

Bagdas, D., Targowska-Duda, K.M., López, J.J., Pérez, E.G., Arias, H.R., and Damaj, M.I. (2015) Antinociceptive and anti-inflammatory properties of 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a positive allosteric modulator of α7 nicotinic acetylcholine receptors, in mice. Anesth. Analg., in press.

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