Browsing by Author "Iturriaga-Vasquez, Patricio"
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- Item2-Arylthiomorpholine derivatives as potent and selective monoamine oxidase B inhibitors(2010) Luhr, Susan; Vilches-Herrera, Marcelo; Fierro Huerta, Angélica; Ramsay, Rona R.; Edmondson, Dale E.; Reyes-Parada, Miguel; Cassels, Bruce K.; Iturriaga-Vasquez, Patricio
- Item3D similarities between the binding sites of monoaminergic target proteins(2018) Nunez-Vivanco, Gabriel; Fierro Huerta, Angélica; Moya, Pablo; Iturriaga-Vasquez, Patricio; Reyes-Parada, Miguel
- Item4-Methylthioamphetamine Increases Dopamine in the Rat Striatum and has Rewarding Effects In Vivo(2012) Sotomayor Zárate, Ramón Eduardo; Quiroz, Gabriel; Araya Gutiérrez, Katherine Angélica; Abarca, Jorge; Ibañez, Maria R.; Montecinos, Alejandro; Guajardo, Carlos; Nuñez, Gabriel; Fierro Huerta, Angélica; Moya, Pablo R.; Iturriaga-Vasquez, Patricio; Gomez-Molina, Cristobal; Gysling Caselli, Katia
- ItemAporphine metho salts as neuronal nicotinic acetylcholine receptor blockers(2007) Iturriaga-Vasquez, Patricio; Pérez Hernández, Edwin Gregorio; Slater, E. Yvonne; Bermudez, Isabel; Cassels, Bruce K.
- ItemCharacterization of a Novel Drosophila SERT Mutant: Insights on the Contribution of the Serotonin Neural System to Behaviors(2017) Hidalgo, Sergio; Molina-Mateo, Daniela; Escobedo, Pia; Zarate, Rafaella V.; Fritz, Elsa; Fierro, Angelica; Perez, Edwin G.; Iturriaga-Vasquez, Patricio; Reyes-Parada, Miguel; Varas, Rodrigo; Fuenzalida-Uribe, Nicolas; Campusano, Jorge M.A better comprehension on how different molecular components of the serotonergic system contribute to the adequate regulation of behaviors in animals is essential in the interpretation on how they are involved in neuropsychiatric and pathological disorders. It is possible to study these components in "simpler" animal models including the fly Drosophila melanogaster, given that most of the components of the serotonergic system are conserved between vertebrates and invertebrates. Here we decided to advance our understanding on how the serotonin plasma membrane transporter (SERT) contributes to serotonergic neurotransmission and behaviors in Drosophila. In doing this, we characterized for the first time a mutant for Drosophila SERT (dSERT) and additionally used a highly selective serotonin-releasing drug, 4-methylthioamphetamine (4-MTA), whose mechanism of action involves the SERT protein. Our results show that dSERT mutant animals exhibit an increased survival rate in stress conditions, increased basal motor behavior, and decreased levels in an anxiety-related parameter, centrophobism. We also show that 4-MTA increases the negative chemotaxis toward a strong aversive odorant, benzaldehyde. Our neurochemical data suggest that this effect is mediated by dSERT and depends on the 4-MTA-increased release of serotonin in the fly brain. Our in silico data support the idea that these effects are explained by specific interactions between 4-MTA and dSERT. In sum, our neurochemical, in silico, and behavioral analyses demonstrate the critical importance of the serotonergic system and particularly dSERT functioning in modulating several behaviors in Drosophila.
- ItemFunctional expression of the α7 and α4-containing nicotinic acetylcholine receptors on the neonatal rat carotid body(2012) Meza, Rodrigo C.; Ortiz, Fernando C.; Bravo, Eduardo; Iturriaga-Vasquez, Patricio; Eugenin, Jaime L.; Varas, RodrigoThe carotid bodies (CBs) are chemosensory organs that respond to hypoxemia with transmitter neurosecretion, leading to a respiratory reflex response. It has been proposed that acetylcholine is a key regulator of transmitter release through activation of presynaptic nicotinic acetylcholine receptors (nAChRs). In the present work, we studied the identity of such nAChRs and their contribution to catecholamine release from CBs.
- ItemImproving Amphetamine Therapeutic Selectivity: N,N-dimethyl-MTA has Dopaminergic Effects and does not Produce Aortic Contraction(2014) Sotomayor-Zarate, Ramon; Jara, Pablo; Araos, Patricio; Vinet, Raul; Quiroz, Gabriel; Renard, Georgina M.; Espinosa, Pedro; Hurtado-Guzman, Claudio; Moya, Pablo R.; Iturriaga-Vasquez, Patricio; Gysling, Katia; Reyes-Parada, MiguelAmphetamine derivatives have therapeutic potential in diseases such as attention deficit hyperactivity disorder, narcolepsy and obesity. However, their prolonged use has been associated with cardiovascular toxicity and addiction. In recent years, we have studied the pharmacological effects of amphetamine derivatives such as methylthioamphetamine (MTA) and N,N-dimethyl-thioamphetamine, with the aim of improving their therapeutic selectivity. In this work, we show that similarly to MTA, N,N-dimethyl-thioamphetamine has effects on the dopamine system, producing a significant increase in extracellular levels of dopamine (as measured by in vivo brain microdialysis) and locomotor activity, which is a behavioural measure of dopaminergic activation. However, unlike MTA, N,N-dimethyl- thioamphetamine does not produce aortic contraction in vitro. Our results show that N,N-dimethyl-thioamphetamine is a drug that retains the dopaminergic effects of amphetamine derivatives but exhibits a lower potential for producing cardiovascular side effects.
- ItemNeonicotinic analogues: Selective antagonists for α4β2 nicotinic acetylcholine receptors(2013) Faundez-Parraguez, Manuel; Farias-Rabelo, Nicolas; Pablo Gonzalez-Gutierrez, Juan; Etcheverry-Berrios, Alvaro; Alzate-Morales, Jans; Adasme-Carreno, Francisco; Varas, Rodrigo; Bermudez, Isabel; Iturriaga-Vasquez, PatricioNicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively used as a template for the synthesis of alpha 4 beta 2-preferring nAChRs. Here, we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel alpha 4 beta 2-preferring neonicotinic ligands. We increased the distance between the basic nitrogen and aromatic group of nicotine by introducing an ester functionality that also mimics acetylcholine (Fig. 2). Additionally, we introduced a benzyloxy group linked to the benzoyl moiety. Although the neonicotinic compounds fully inhibited binding of both [alpha-I-125]bungarotoxin to human alpha 7 nAChRs and [H-3]cytisine to human alpha 4 beta 2 nAChRs, they were markedly more potent at displacing radioligand binding to human alpha 4 beta 2 nAChRs than to alpha 7 nAChRs. Functional assays showed that the neonicotinic compounds behave as antagonists at alpha 4 beta 2 and alpha 4 beta 2 alpha 5 nAChRs. Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for alpha 4 beta 2 or alpha 4 beta 2 alpha 5 nAChRs. Docking of the compounds on homology models of the agonist binding site at the alpha 4/beta 2 subunit interfaces of alpha 4 beta 2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site. (C) 2013 Elsevier Ltd. All rights reserved.
- ItemSynthesis and Biological Screening of Novel Indolalkyl Arenes Targeting the Serotonine Transporter(2014) Ojeda-Gomez, Claudia; Pessoa-Mahana, Hernan; Iturriaga-Vasquez, Patricio; David Pessoa-Mahana, Carlos; Recabarren-Gajardo, Gonzalo; Mendez-Rojas, ClaudioA series of functionalized indolylalkylarenes 3-16(a and b) were synthesized and their affinities for the serotonin transporter were investigated in vitro. Compounds 3-12(a and b) were obtained by nucleophilic substitution of 3-(1H-indol-3-yl)propyl-4-methylbenzenesulfonates 2(a and b) with a series of azaheterocycles. Compounds 14-16(a and b) were prepared in a two-step sequence by reaction of 3-(1H-indol-3-yl)-2-methylpropanal with substituted 1,2-phenylenediamines. Compounds 3b, 4b, and 5b showed good binding affinities (K-i=33.0, 48.0, and 17nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies.
- ItemSynthesis, docking and pharmacological evaluation of novel homo- and hetero-bis 3-piperazinylpropylindole derivatives at SERT and 5-HT1A receptor(2013) Pessoa-Mahana, Hernan; Gonzalez-Lira, Christian; Fierro, Angelica; Zapata-Torres, Gerald; David Pessoa-Mahana, C.; Ortiz-Severin, Javiera; Iturriaga-Vasquez, Patricio; Reyes-Parada, Miguel; Silva-Matus, Paul; Saitz-Barria, Claudio; Araya-Maturana, RamiroA series of 3-(3-(4-(3-(1H-indol-3-yl)propyl)piperazin-1-yl)propyl)-1H-indole derivatives (3a-d and 5a-f) as homo-and hetero-bis-ligands, were synthesized and evaluated for in vitro affinity at the serotonin transporter (SERT) and the 5-HT1A receptor. Compounds 5b and 5f showed nanomolar affinities for both targets. The experimental data were rationalized according to results obtained from docking experiments. These findings are in agreement with our proposal that bis-indole derivatives can bind both targets, and might serve as leads in the quest of ligands endowed with a dual mechanism of action. (C) 2013 Elsevier Ltd. All rights reserved.