Patricio Iturriaga Vásquez | Universidad de Chile (original) (raw)

Papers by Patricio Iturriaga Vásquez

Biomedicines

Alcoholism is a worldwide public health problem with high economic cost and which affects health ... more Alcoholism is a worldwide public health problem with high economic cost and which affects health and social behavior. It is estimated that alcoholism kills 3 million people globally, while in Chile it is responsible for around 9 thousand deaths per year. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels expressed in the central nervous system, and they were suggested to modulate the ethanol mechanism involved in abuse and dependence. Previous work demonstrated a short-term treatment with UFR2709, a nAChRs antagonist, which reduced ethanol intake using a two-bottle free-choice paradigm in University of Chile bibulous (UChB) rats. Here, we present evidence of the UFR2709 efficacy in reducing the acquisition and long-term ethanol consumption. Our results show that UFR2709 (2.5 mg/kg i.p.) reduces the seek behavior and ethanol intake, even when the drug administration was stopped, and induced a reduction in the overall ethanol intake by around 55%. Using naïve UCh...

Evidence from systems biology indicates that promiscuous drugs, i.e. those that act simulta-neous... more Evidence from systems biology indicates that promiscuous drugs, i.e. those that act simulta-neously at various protein targets, are clinically better in terms of efficacy, than those that act in a more selective fashion. This has generated a new trend in drug development called polypharmacology. However, the rational design of promiscuous compounds is a difficult task, particularly when the drugs are aimed to act at receptors with diverse structure, func-tion and endogenous ligand. In the present work, using docking and molecular dynamics methodologies, we established the most probable binding sites of SB-206553, a drug origi-nally described as a competitive antagonist of serotonin type 2B/2C metabotropic receptors (5-HT2B/2CRs) and more recently as a positive allosteric modulator of the ionotropic α7 nico-tinic acetylcholine receptor (nAChR). To this end, we employed the crystal structures of the 5-HT2BR and acetylcholine binding protein as templates to build homology models of the...

Molecules, 2019

Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporte... more Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4β2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 μM for h-DAT and 0.031 ± 0.006 μM for α4β2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed K...

This work was supported by ICM grant No P99-031-F and by a research grant from the Generalitat Va... more This work was supported by ICM grant No P99-031-F and by a research grant from the Generalitat Valenciana (GV01-292).

Journal of Biological Chemistry, 2016

A l c a i n o , C. , M u s g a a r d , M. , M i n g u e z , T. , M a z z a f e r r o , S. , F a u... more A l c a i n o , C. , M u s g a a r d , M. , M i n g u e z , T. , M a z z a f e r r o , S. , F a u n d e z , M. , I t u r r i a g a-V a s q u e z , P. , B i g g i n , P. a n d B e rm u d e z-D i a z , I. (2 0 1 6) ' R o l e o f t h e C y s l o o p a n d t r a n sm em b r a n e d om a i n i n t h e a l l o s t e r i c m o d u l a t i o n o f α 4 β 2 n i c o t i n i c a c e t y l c h o l i n e r e c e p t o r s ' , J o u r n a l o f B i o l o g i c a l C h em i s t r y , 2 9 2 (2) , p p. 5 5 1-5 6 2 .

Neurotoxicity Research, 2010

In previous studies, we observed that cells treated with aminochrome obtained by oxidizing dopami... more In previous studies, we observed that cells treated with aminochrome obtained by oxidizing dopamine with oxidizing agents dramatically changed cell morphology, thus posing the question if such morphological changes were dependent on aminochrome or the oxidizing agents used to produce aminochrome. Therefore, to answer this question, we have now purified aminochrome on a CM-Sepharose 50-100 column and, using NMR studies, we have confirmed that the resulting aminochrome was pure and that it retained its structure. Fluorescence microscopy with calcein-AM and transmission electron microscopy showed that RCSN-3 cells presented an elongated shape that did not change when the cells were incubated with 50 muM aminochrome or 100 muM dicoumarol, an inhibitor of DT-diaphorase. However, the cell were reduced in size and the elongated shape become spherical when the cells where incubated with 50 muM aminochrome in the presence of 100 muM dicoumarol. Under these conditions, actin, alpha-, and beta-tubulin cytoskeleton filament networks became condensed around the cell membrane. Actin aggregates were also observed in cells processes that connected the cells in culture. These results suggest that aminochrome one-electron metabolism induces the disruption of the normal morphology of actin, alpha-, and beta-tubulin in the cytoskeleton, and that DT-diaphorase prevents these effects.

Bioorganic & Medicinal Chemistry, 2007

(S)-Aporphine metho salts with the 1,2,9,10 oxygenation pattern displaced radioligands from recom... more (S)-Aporphine metho salts with the 1,2,9,10 oxygenation pattern displaced radioligands from recombinant human alpha7 and alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChR) at low micromolar concentrations. The affinity of the nonphenolic glaucine methiodide (4) (vs [(3)H]cytisine) was the lowest at alpha4beta2 nAChR (K(i)=10 microM), and predicentrine methiodide (2) and xanthoplanine iodide (3), with free hydroxyl groups at C-2 or C-9, respectively, had the highest affinity at these receptors (K(i) approximately 1 microM), while the affinity of the diphenolic boldine methiodide (1) was intermediate between these values. At homomeric alpha7 nAChR, xanthoplanine had the highest affinity (K(i)=10 microM) vs [(125)I]alpha-bungarotoxin while the other three compounds displaced the radioligand with K(i) values between 15 and 21 microM. At 100 microM, all four compounds inhibited the responses of these receptors to EC(50) concentrations of ACh. The effects of xanthoplanine iodide (3) were studied in more detail. Xanthoplanine fully inhibited the EC(50) ACh responses of both alpha7 and alpha4beta2 nACh receptors with estimated IC(50) values of 9+/-3 microM (alpha7) and 5+/-0.8 microM (alpha4beta2).

Journal of Biological Chemistry, 2014

Background: The ␣4/␤2 and ␣4/␣4 interfaces of the (␣4␤2) 2 ␣4 nicotinic acetylcholine receptor ho... more Background: The ␣4/␤2 and ␣4/␣4 interfaces of the (␣4␤2) 2 ␣4 nicotinic acetylcholine receptor house structurally different agonist sites. Results: Agonists of a certain size cannot bind the ␣4/␣4 interface, which decreases efficacy. Conclusion: The ability to bind all agonist sites in (␣4␤2) 2 ␣4 receptors critically influences agonist efficacy. Significance: The finding adds a new level of complexity to structural mechanisms governing agonist efficacy. * This work was supported by Oxford Brookes University funding (to I. B.,

Zeitschrift für Kristallographie - New Crystal Structures, 2005

Expert Opinion on Drug Discovery, 2016

Polypharmacology, which refers to the ability of a molecule to simultaneously interact with multi... more Polypharmacology, which refers to the ability of a molecule to simultaneously interact with multiple target proteins, is shifting the drug discovery process from a 'one-drug-one-target' paradigm to a conceptual framework in which the multitarget profile of small molecules is proactively pursued. Nicotinic acetylcholine receptors (nAChRs) appear as attractive targets for the design of polypharmacological agents. These proteins participate in the regulation of multiple physiological processes and impressive progress has been made regarding their structure and function. Moreover, they contain several ligand binding sites, and a number of compounds including orthosteric and allosteric ligands, have been described. The authors provide an overview of some of these topics and briefly discuss the mechanisms of action of some known promiscuous drugs that act at nAChRs, with the idea that this analysis will serve to guide the development of novel polypharmacological agents with a wide spectrum of actions. The authors anticipate that many innovative drugs will be compounds intentionally designed to have polypharmacological properties. Furthermore, the authors suggest that although the search for multitarget drugs acting at the orthosteric site of nAChRs will remain an interesting option, allosteric sites of these receptors exhibit a much greater polypharmacological potential.

A simple synthetic route for the preparation of 2-phenyl-I,3-propanediamines, based on a Knoevena... more A simple synthetic route for the preparation of 2-phenyl-I,3-propanediamines, based on a Knoevenagel-Michael double .:ondensation followed by reduction, was developed using nitromethane as reagent and solvent, and sodium bicarbonate as base in ¡he first step, followed by catalytic hydrogenation over Adams catalyst.This work was supported by ICM grant W P99-03I-F and FONDECYT grant N° 1040776

Journal of Enzyme Inhibition and Medicinal Chemistry, 2003

(6)-4-Methylthioamphetamine (MTA) was resolved into its enantiomers, and a series of N-alkyl deri... more (6)-4-Methylthioamphetamine (MTA) was resolved into its enantiomers, and a series of N-alkyl derivatives of the parent compound, as well as its a-ethyl analogue, were prepared. The monoamine oxidase (MAO) inhibitory properties of these substances were evaluated in vitro, using a crude rat brain mitochondrial suspension as the source of enzyme. All compounds produced a selective, reversible and concentration-related inhibition of MAO-A. (1)-MTA proved to be the most potent inhibitor studied, while all the other derivatives were less active than the parent compound, with (2)-MTA being about 18 times less potent than the (1) isomer. The analysis of structure-activity relationships indicates that the introduction of alkyl substituents on the amino group of MTA leads to a reduction in the potency of the derivatives as MAO-A inhibitors, an effect which increases with the size of the substituent.

Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 2007

Current knowledge of the biochemistry of Trypanosoma cruzi has led to the development of new drug... more Current knowledge of the biochemistry of Trypanosoma cruzi has led to the development of new drugs and the understanding of their mode of action. Some trypanocidal drugs such as nifurtimox and benznidazole act through free radical generation during their metabolism. T. cruzi is very susceptible to the cell damage induced by these metabolites because enzymes scavenging free radicals are absent or have very low activities in the parasite. Another potential target is the biosynthetic pathway of glutathione and trypanothione, the low molecular weight thiol found exclusively in trypanosomatids. These thiols scavenge free radicals and participate in the conjugation and detoxication of numerous drugs. Inhibition of this key pathway could render the parasite much more susceptible to the toxic action of drugs such as nifurtimox and benznidazole without affecting the host significantly. Other drugs such as allopurinol and purine analogs inhibit purine transport in T. cruzi, which cannot synthesize purines de novo. Nitroimidazole derivatives such as itraconazole inhibit sterol metabolism. The parasite's respiratory chain is another potential therapeutic target because of its many differences with the host enzyme complexes. The pharmacological modulation of the host's immune response against T. cruzi infection as a possible chemotherapeutic target is discussed. A large set of chemicals of plant origin and a few animal metabolites active against T. cruzi are enumerated and their likely modes of action are briefly discussed.

British Journal of Pharmacology, 2005

Effects of derivatives of coclaurine (C), which mimic the 'eastern' or the nonquaternary halves o... more Effects of derivatives of coclaurine (C), which mimic the 'eastern' or the nonquaternary halves of the alkaloids tetrandrine or d-tubocurarine, respectively, both of which are inhibitors of nicotinic acetylcholine receptors (nACh), were examined on recombinant, human a7, a4b2 and a4b4 nACh receptors expressed in Xenopus oocytes and clonal cell lines using two-electrode voltage clamping and radioligand binding techniques. 2 In this limited series, Cs have higher affinity and are most potent at a4 subunit-containing-nACh receptors and least potent at homomeric a7 receptors, and this trend is very marked for the N-unsubstituted C and its O,O 0-bisbenzyl derivative. 3 7-O-Benzyl-N-methylcoclaurine (BBCM) and its 12-O-methyl derivative showed the highest affinities and potencies at all three receptor subtypes, and this suggests that lipophilicity at C7 and/or C12 increases potency. 4 Laudanosine and armepavine (A) were noncompetitive and voltage-dependent inhibitors of a7, a4b2 or a4b4 receptors, but the bulkier C7-benzylated 7BNMC (7-O-benzyl-N-methylcoclaurine) and 7B12MNMC (7-O-benzyl-N,12-O-dimethyl coclaurine) were voltage-independent, noncompetitive inhibitors of nACh receptors. Voltage-dependence was also lost on going from A to its N-ethyl analogue. 5 These studies suggest that C derivatives may be useful tools for studies characterising the antagonist and ion channel sites on human a7, a4b2 or a4b4 nACh receptors and for revealing structure-function relationships for nACh receptor antagonists.

Brain Research, 2006

Petrosal ganglion neurons are depolarized and fire action potentials in response to acetylcholine... more Petrosal ganglion neurons are depolarized and fire action potentials in response to acetylcholine and nicotine. However, little is known about the subtype(s) of nicotinic acetylcholine receptors involved, although α4 and α7 subunits have been identified in petrosal ganglion neurons. Cytisine, an alkaloid unrelated to nicotine, and its bromo derivatives are agonists exhibiting different affinities, potencies and efficacies at nicotinic acetylcholine receptors containing α4 or α7 subunits. To characterize the receptors involved, we studied the effects of these agonists and the nicotinic acetylcholine receptor antagonists hexamethonium and α-bungarotoxin in isolated petrosal ganglion neurons. Petrosal ganglia were excised from anesthetized cats and cultured for up to 16 days. Using patch-clamp technique, we recorded whole-cell currents evoked by 5-10 s applications of acetylcholine, cytisine or its bromo derivatives. Agonists and antagonists were applied by gravity from a pipette near the neuron surface. Neurons responded to acetylcholine, cytisine, 3-bromocytisine and 5-bromocytisine with fast inward currents that desensitized during application of the stimuli and were reversibly blocked by 1 μM hexamethonium or 10 nM α-bungarotoxin. The order of potency of the agonists was 3-bromocytisine ≫ acetylcholine ≅ cytisine ≫ 5-bromocytisine, suggesting that homomeric α7 neuronal nicotinic receptors predominate in cat petrosal ganglion neurons in culture.

Archiv der Pharmazie, 2013

A series of functionalized indolylalkylarenes 3-16(a and b) were synthesized and their affinities... more A 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 ¼ 33.0, 48.0, and 17 nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies.

Nicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively us... more Nicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively used as a template for the synthesis of a4b2-prefer ring nAChRs. Here, we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel a4b2-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 [a-125 I]bungarotoxin to human a7 nAChRs and [ 3 H]cytisine to human a4b2 nAChRs, they were markedly more potent at displacing radioligand bindi ng to human a4b2 nAChRs than to a7 nAChRs. Functional assays showed that the neonicotinic compounds behave as antagonists at a4b2 and a4b2a5 nAChRs. Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for a4b2 or a4b2a5 nAChRs. Docking of the compounds on homology models of the agonist binding site at the a4/b2 subunit interfaces of a4b2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site.

Journal of Neurochemistry, 2005

Condensation of 4-methylthiobenzaldehyde with 1-nitropropane unexpectedly afforded separable amou... more Condensation of 4-methylthiobenzaldehyde with 1-nitropropane unexpectedly afforded separable amounts of both (E)and (Z)-1-(4-methylthiophenyl)-2-nitrobutene. The 1H and 13C NMR spectra allowed the unequivocal assignment of all signals and their correlation with the preferred conformations adopted by these compounds as determined by NOESY experiments. Hartree Fock theory optimizations at the 6-311G(d,p) level were carried out for the stereoisomeric 4-methylthionitroethene, -nitropropene, and -nitrobutene pairs, and the relative energy differences between isomers were calculated in order to estimate approximate E/Z equilibrium constants. These energy differences decrease with the increasing number of side chain carbon atoms, explaining the possibility of separating (E)and (Z)-nitrobutenes and the failure to isolate the (Z) isomers of the lower homologues under the usual thermodynamically controlled reaction conditions.