9 research outputs found
2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands
Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new dopamine receptors (DR) acting drugs as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) and tetrahydroprotoberberines (THPBs) can behave as selective D2 dopaminergic alkaloids since they share structural similarities with dopamine. In the present study we have synthesized eleven 2,3,9- and 2,3,11-trisubstituted THPB compounds (six of them are described for the first time) and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR and establish the structure-activity relationship (SAR) as dopaminergic agents. In general, all the tested THPBs with protected phenolic hydroxyls showed a lower affinity for D1 and D2 DR than their corresponding homologues with free hydroxyl groups. In previous studies in which dopaminergic affinity of 1-benzyl-THIQs (BTHIQs) was evaluated, the presence of a Cl into the A-ring resulted in increased affinity and selectivity towards D2 DR. This is in contrast with the current study since the existence of a chlorine atom into the A-ring of the THPBs caused increased affinity for D1 DR but dramatically reduced the selectivity for D2 DR. An OH group in position 9 of the THPB (9f) resulted in a higher affinity for DR than its homologue with an OH group in position 11 (9e) (250 fold for D2 DR). None of the compounds showed any cytotoxicity in freshly isolated human neutrophils. A molecular modelling study of three representative THPBs was carried out. The combination of MD simulations with DFT calculations provided a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compound 9d (2,3,9-trihydroxy-THPB) behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation
Intraoperative oxygen tension and redox homeostasis in Pseudomyxoma peritonei: A short case series
IntroductionPseudomyxoma peritonei (PMP) is a rare malignant disease characterized by a massive multifocal accumulation of mucin within the peritoneal cavity. The current treatment option is based on complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. However, the recurrence is frequent with subsequent progression and death. To date, most of the studies published in PMP are related to histological and genomic analyses. Thus, the need for further studies unveiling the underlying PMP molecular mechanisms is urgent. In this regard, hypoxia and oxidative stress have been extensively related to tumoral pathologies, although their contribution to PMP has not been elucidated.MethodsIn this manuscript, we have evaluated, for the first time, the intratumoral real-time oxygen microtension (pO2mt) in the tumor (soft and hard mucin) and surrounding healthy tissue from five PMP patients during surgery. In addition, we measured hypoxia (Hypoxia Inducible Factor-1a; HIF-1α) and oxidative stress (catalase; CAT) markers in soft and hard mucin from the same five PMP patient samples and in five control samples.ResultsThe results showed low intratumoral oxygen levels, which were associated with increased HIF-1α protein levels, suggesting the presence of a hypoxic environment in these tumors. We also found a significant reduction in CAT activity levels in soft and hard mucin compared with healthy tissue samples.DiscussionIn conclusion, our study provides the first evidence of low intratumoral oxygen levels in PMP patients associated with hypoxia and oxidative stress markers. However, further investigation is required to understand the potential role of oxidative stress in PMP in order to find new therapeutic strategies
Amyloid-β fibril disruption by C \u3c inf\u3e 60 - Molecular guidance for rational drug design
The WHO has listed Alzheimer\u27s disease among the major neurological disorders with an estimated 35 million people affected worldwide. Amyloid-β is mostly believed to be the causative factor in Alzheimer\u27s disease and the severity of the disease correlates with the tendency of amyloid-β to form aggregation patterns - plaques. Lacking effective medication, the identification of any underlying mechanistic principles regarding plaque formation appears to be crucial. Here we carry out computer simulations to study the effect of C 60 on structure and stability of an idealised pentameric construct of amyloid-β units (a model fibril). A binding site on top of the structurally ordered stack of β-sheets is identified that triggers structural alterations at the turn region of the hook-like β-sheet assembly. Significant structural alterations are: (i) the destruction of regular helical twist, (ii) the loss of a stabilizing salt bridge and (iii) the loss of a stabilizing hydrophobic interaction close to the turn. Consequently, the main effect of C 60 is the induction of sizable destabilization in native fibril structure. These structural insights may serve as a molecular guide for further rational drug design of effective inhibitors targeting fibril formation in Alzheimer\u27s disease. This journal is © the Owner Societies 2012
Virtual and Remote Robotic Laboratory Using EJS, MATLAB and LabVIEW
This paper describes the design and implementation of a virtual and remote laboratory based on Easy Java Simulations (EJS) and LabVIEW. The main application of this laboratory is to improve the study of sensors in Mobile Robotics, dealing with the problems that arise on the real world experiments. This laboratory allows the user to work from their homes, tele-operating a real robot that takes measurements from its sensors in order to obtain a map of its environment. In addition, the application allows interacting with a robot simulation (virtual laboratory) or with a real robot (remote laboratory), with the same simple and intuitive graphical user interface in EJS. Thus, students can develop signal processing and control algorithms for the robot in simulation and then deploy them on the real robot for testing purposes. Practical examples of application of the laboratory on the inter-University Master of Systems Engineering and Automatic Control are presented
Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice.
International audienceThree series of 1-substituted-7-chloro-6-hydroxy-tetrahydroisoquinolines (1-butyl-, 1-phenyl- and 1-benzyl derivatives) were prepared to explore the influence of each of these groups at the 1-position on the affinity for dopamine receptors. All the compounds displayed affinity for D(1)-like and/or D(2)-like dopamine receptors in striatal membranes, and were unable to inhibit [(3)H]-dopamine uptake in striatal synaptosomes. Different structure requirements have been observed for adequate D(1) or D(2) affinities. This paper details the synthesis, structural elucidation, dopaminergic binding assays, structure-activity relationships (SAR) of these three series of isoquinolines. Moreover, 1-butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline (1e) with the highest affinity towards D(2)-like receptors (K(i) value of 66nM) and the highest selectivity (49-fold D(2) vs D(1)) by in vitro binding experiments was then evaluated in behavioral assays (spontaneous activity and forced swimming test) in mice. Compound 1e increased locomotor activity in a large dose range (0.04-25mg/kg). Furthermore, this lead compound produced reduction in immobility time in the forced swimming test at a dose (0.01mg/kg) that did not modify locomotor activity. The haloperidol (0.03mg/kg), a D(2) receptor preferred antagonist, blocked the antidepressant-like effect of compound 1e
Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor
[EN] A series of tetrahydroisoquinolines functionalized with carbamates is reported here as highly selective ligands on the dopamine D2 receptor. These compounds were selected by means of a molecular modeling study. The studies were carried out in three stages: first an exploratory study was carried out using combined docking techniques and molecular dynamics simulations. According to these results, the bioassays were performed; these experimental studies corroborated the results obtained by molecular modeling. In the last stage of our study, a QTAIM analysis was performed in order to determine the main molecular interactions that stabilize the different ligand-receptor complexes. Our results show that the adequate use of combined simple techniques is a very useful tool to predict the potential affinity of new ligands at dopamine D1 and D2 receptors. In turn the QTAIM studies show that they are very useful to evaluate in detail the molecular interactions that stabilize the different ligand-receptor complexes; such information is crucial for the design of new ligands.This work was supported by Universidad Nacional de San Luis (UNSL) and CONICET grants 2-1214 and PIP444, respectively. E.L.A, L.J.G, S.A.A and R.D.E are staff members of the National Scientific and Technical Research Council - Argentina ( CONICET, Argentina).Parravicini, O.; Bogado, ML.; Rojas, S.; Angelina, EL.; Andujar, SA.; Gutierrez, LJ.; Cabedo Escrig, N.... (2017). Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor. Journal of Molecular Modeling. 23(9):1-14. https://doi.org/10.1007/s00894-017-3441-6S114239Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63(1):182–217. https://doi.org/10.1124/pr.110.002642Luthra PM, Kumar JBS (2012) Plausible improvements for selective targeting of dopamine receptors in therapy of Parkinson’s disease. Mini-Rev Med Chem 12(14):1556–1564. https://doi.org/10.2174/138955712803832645Poewe W (2009) Treatments for Parkinson disease-past achievements and current clinical needs. Neurology 72 (7 SUPPL. 2):S65-S73. https://doi.org/10.1212/WNL.0b013e31819908ceSeeman P, Watanabe M, Grigoriadis D (1985) Dopamine D2 receptor binding sites for agonists: a tetrahedral model. Mol Pharmacol 28(5):391–399McDonald WM, Sibley DR, Kilpatrick BF, Caron MG (1984) Dopaminergic inhibition of adenylate cyclase correlates with high affinity agonist binding to anterior pituitary D2 dopamine receptors. Mol Cell Endocrinol 36(3):201–209. https://doi.org/10.1016/0303-7207(84)90037-6Mottola DM, Laiter S, Watts VJ, Tropsha A, Wyrick SD, Nichols DE, Mailman RB (1996) Conformational analysis of D1 dopamine receptor agonists: pharmacophore assessment and receptor mapping. J Med Chem 39(1):285–296. https://doi.org/10.1021/jm9502100Alkorta I, Villar HO (1993) Considerations on the recognition of the D1 receptor by agonists. J Comput Aided Mol Des 7(6):659–670. https://doi.org/10.1007/BF00125324Cueva JP, Giorgioni G, Grubbs RA, Chemel BR, Watts VJ, Nichols DE (2006) Trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist. J Med Chem 49(23):6848–6857. https://doi.org/10.1021/jm0604979Negash K, Nichols DE, Watts VJ, Mailman RB (1997) Further definition of the D1 dopamine receptor pharmacophore: synthesis of trans-6,6a,7,8,9,13b-hexahydro-5h-benzo[d]naphth[2,1-b]azepines as rigid analogues of β-phenyldopamine. J Med Chem 40(14):2140–2147. https://doi.org/10.1021/jm970157aPettersson I, Liljefors T (1987) Structure-activity relationships for apomorphine congeners. Conformational energies vs. biological activities. J Comput Aided Mol Des 1(2):143–152. https://doi.org/10.1007/BF01676958Tonani R, Dunbar Jr J, Edmonston B, Marshall GR (1987) Computer-aided molecular modeling of a D2-agonist dopamine pharmacophore. J Comput Aided Mol Des 1(2):121–132. https://doi.org/10.1007/BF01676956Mewshaw RE, Kavanagh J, Stack G, Marquis KL, Shi X, Kagan MZ, Webb MB, Katz AH, Park A, Kang YH, Abou-Gharbia M, Scerni R, Wasik T, Cortes-Burgos L, Spangler T, Brennan JA, Piesla M, Mazandargmi H, Cockett MI, Ochalski R, Coupet J, Andree TH (1997) New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans. J Med Chem 40(26):4235–4256. https://doi.org/10.1021/jm9703653Chidester CG, Lin CH, Lahti RA, Haadsma-Svensson SR, Smith MW (1993) Comparison of 5-HT1A and dopamine D2 pharmacophores. X-ray structures and affinities of conformationally constrained ligands. J Med Chem 36(10):1301–1315Alkorta I, Villar HO (1994) Molecular electrostatic potential of d1 and d2 dopamine agonists. J Med Chem 37(1):210–213Wilcox RE, Tseng T, Brusniak MYK, Ginsburg B, Pearlman RS, Teeter M, Durand C, Starr S, Neve KA (1998) CoMFA-based prediction of agonist affinities at recombinant D1 vs D2 dopamine receptors. J Med Chem 41(22):4385–4399. https://doi.org/10.1021/jm9800292El Aouad N, Berenguer I, Romero V, Marín P, Serrano A, Andujar S, Suvire F, Bermejo A, Ivorra MD, Enriz RD, Cabedo N, Cortes D (2009) Structure-activity relationship of dopaminergic halogenated 1-benzyl-tetrahydroisoquinoline derivatives. Eur J Med Chem 44(11):4616–4621. https://doi.org/10.1016/j.ejmech.2009.06.033Berenguer I, Aouad NE, Andujar S, Romero V, Suvire F, Freret T, Bermejo A, Ivorra MD, Enriz RD, Boulouard M, Cabedo N, Cortes D (2009) Tetrahydroisoquinolines as dopaminergic ligands: 1-butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice. Bioorg Med Chem 17(14):4968–4980. https://doi.org/10.1016/j.bmc.2009.05.079Andujar S, Suvire F, Berenguer I, Cabedo N, Marin P, Moreno L, Dolores Ivorra M, Cortes D, Enriz RD (2012) Tetrahydroisoquinolines acting as dopaminergic ligands. A molecular modeling study using MD simulations and QM calculations. J Mol Model 18(2):419–431. https://doi.org/10.1007/s00894-011-1061-0Angelina E, Andujar S, Tosso RD, Enriz RD, Peruchena N (2014) Non-covalent interactions in receptor–ligand complexes. A study based on the electron charge density. J Phys Org Chem 27:128–134Parraga J, Cabedo N, Andujar S, Piqueras L, Moreno L, Galan A, Angelina E, Enriz RD, Ivorra MD, Sanz MJ, Cortes D (2013) 2,3,9- and 2,3,11-trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands. Eur J Med Chem 68:150–166Andujar SA, de Angel BM, Charris JE, Israel A, Suarez-Roca H, Lopez SE, Garrido MR, Cabrera EV, Visbal G, Rosales C, Suvire FD, Enriz RD, Angel-Guio JE (2008) Synthesis, dopaminergic profile, and molecular dynamics calculations of N-aralkyl substituted 2-aminoindans. Bioorg Med Chem 16(6):3233–3244Párraga J, Andujar SA, Rojas S, Gutierrez LJ, El Aouad N, Sanz MJ, Enriz RD, Cabedo N, Cortes D (2016) Dopaminergic isoquinolines with hexahydrocyclopenta[ij]-isoquinolines as D2−like selective ligands. Eur J Med Chem 122:27-42. https://doi.org/10.1016/j.ejmech.2016.06.009Galán A, Moreno L, Párraga J, Serrano Á, Sanz MJ, Cortes D, Cabedo N (2013) Novel isoquinoline derivatives as antimicrobial agents. Bioorg Med Chem 21(11):3221–3230. https://doi.org/10.1016/j.bmc.2013.03.042Malo M, Brive L, Luthman K, Svensson P (2010) Selective pharmacophore models of dopamine D1 and D2 full agonists based on extended pharmacophore features. ChemMedChem 5(2):232–246. https://doi.org/10.1002/cmdc.200900398Lan H, DuRand CJ, Teeter MM, Neve KA (2006) Structural determinants of pharmacological specificity between D 1 and D2 dopamine receptors. Mol Pharmacol 69(1):185–194. https://doi.org/10.1124/mol.105.017244Neve KA, Cumbay MG, Thompson KR, Yang R, Buck DC, Watts VJ, Durand CJ, Teeter MM (2001) Modeling and mutational analysis of a putative sodium-binding pocket on the dopamine D2 receptor. Mol Pharmacol 60(2):373–381Kalani MYS, Vaidehi N, Hall SE, Trabanino RJ, Freddolino PL, Kalani MA, Floriano WB, Wai Tak Kam V, Goddard Iii WA (2012) The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists. Proc Natl Acad Sci USA 101:3815–3820Becker OM, Marantz Y, Shacham S, Inbal B, Heifetz A, Kalid O, Bar-Haim S, Warshaviak D, Fichman M, Noiman S (2004) G protein-coupled receptors: in silico, drug discovery in 3D. Proc Natl Acad Sci USA 101(31):11304–11309. https://doi.org/10.1073/pnas.0401862101Micheli F, Bonanomi G, Blaney FE, Braggio S, Capelli AM, Checchia A, Curcuruto O, Damiani F, Di Fabio R, Donati D, Gentile G, Gribble A, Hamprecht D, Tedesco G, Terreni S, Tarsi L, Lightfoot A, Stemp G, MacDonald G, Smith A, Pecoraro M, Petrone M, Perini O, Piner J, Rossi T, Worby A, Pilla M, Valerio E, Griffante C, Mugnaini M, Wood M, Scott C, Andreoli M, Lacroix L, Schwarz A, Gozzi A, Bifone A, Ashby Jr CR, Hagan JJ, Heidbreder C (2007) 1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D3 receptor antagonists. J Med Chem 50(21):5076–5089. https://doi.org/10.1021/jm0705612Párraga J, Cabedo N, Andujar S, Piqueras L, Moreno L, Galán A, Angelina E, Enriz RD, Ivorra MD, Sanz MJ, Cortes D (2013) 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands. Eur J Med Chem. 68:150-166. https://doi.org/10.1016/j.ejmech.2013.07.036Angelina E, Andujar S, Moreno L, Garibotto F, Párraga J, Peruchena N, Cabedo N, Villecco M, Cortes D, Enriz RD (2015) 3-chlorotyramine acting as ligand of the D2 dopamine receptor. Molecular modeling, synthesis and D2 receptor affinity. Molec Inform 34 (1):28-43. https://doi.org/10.1002/minf.201400093Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE (2010) Improved side-chain torsion potentials for the amber ff99SB protein force field. Proteins 78(8):1950–1958. https://doi.org/10.1002/prot.22711Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174Case DA, Darden TA, Cheatham III TE, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts B, Hayik S, Roitberg A, Seabra G, Swails J, Goetz AW, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wolf RM, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh M-J, Cui G, Roe DR, Mathews DH, Seetin MG, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA (2012) AMBER12. University of California, San FranciscoRyckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23(3):327–341. https://doi.org/10.1016/0021-9991(77)90098-5Izaguirre JA, Catarello DP, Wozniak JM, Skeel RD (2001) Langevin stabilization of molecular dynamics. J Chem Phys 114(5):2090–2098. https://doi.org/10.1063/1.1332996Essmann U, Perera L, Berkowitz M, Darden T, Lee H, Pedersen L (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593Hou T, Li N, Li Y, Wang W (2012) Characterization of domain-peptide interaction interface: prediction of SH3 domain-mediated protein-protein interaction network in yeast by generic structure-based models. J Proteome Res 11(5):2982–2995Gohlke H, Kiel C, Case DA (2003) Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. J Mol Biol 330(4):891–913Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Jr., Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09 revision D.01. Gaussian Inc, WallingfordBader RFW (1994) Atoms in molecules: a quantum theory. Clarendon, OxfordLu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33(5):580–592Case DA, Cheatham Iii TE, Darden T, Gohlke H, Luo R, Merz Jr KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The amber biomolecular simulation programs. J Comput Chem 26(16):1668–1688. https://doi.org/10.1002/jcc.20290Angel Guio JE, Santiago A, Rossi R, Migliore de Angel B, Barolo S, Andujar S, Hernandez V, Rosales C, Charris JE, Suarez-Roca H, Israel A, Ramirez MM, Ortega J, Cano NH, Enriz RD (2011) Synthesis and preliminary pharmacological evaluation of methoxilated indoles with possible dopaminergic central action. Lat Am J Pharm 30(10):1934Andujar SA, Tosso RD, Suvire FD, Angelina E, Peruchena N, Cabedo N, Cortes D, Enriz RD (2012) Searching the “biologically relevant” conformation of dopamine: a computational approach. J Chem Inf Model 52(1):99–112. https://doi.org/10.1021/ci2004225Sealfon SC, Chi L, Ebersole BJ, Rodic V, Zhang D, Ballesteros JA, Weinstein H (1995) Related contribution of specific helix 2 and 7 residues to conformational activation of the serotonin 5-HT2A receptor. J Biol Chem 270(28):16683–16688Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S (2012) Action of molecular switches in GPCRs - theoretical and experimental studies. Curr Med Chem 19(8):1090–1109. https://doi.org/10.2174/092986712799320556Tosso RD, Andujar SA, Gutierrez L, Angelina E, Rodriguez R, Nogueras M, Baldoni H, Suvire FD, Cobo J, Enriz RD (2013) Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration. J Chem Inf Model 53(8):2018–2032Ortiz JE, Pigni NB, Andujar SA, Roitman G, Suvire FD, Enriz RD, Tapia A, Bastida J, Feresin GE (2016) Alkaloids from Hippeastrum Argentinum and their cholinesterase-inhibitory activities: an in vitro and in Silico study. J Nat Prod 79(5):1241–1248. https://doi.org/10.1021/acs.jnatprod.5b00785Luchi AM, Angelina EL, Andujar SA, Enriz RD, Peruchena NM (2016) Halogen bonding in biological context: a computational study of D2 dopamine receptor. J Phys Org Chem 29 (11):645-655. https://doi.org/10.1002/poc.358
Síntesis y evaluación farmacológica preliminar de análogos de índoles fusionado con posible actividad dopaminérgica central
La neurotransmisión dopaminérgica juega un papel importante en los desórdenes que involucran al sistema nerviosocentral (SNC) tales como, la esquizofrenia, la enfermedad de Parkinson, el síndrome de Tourette, las diskinesiastardías y las adicciones psicoestimulantes. La esquizofrenia se manifiesta por un aumento de los niveles de dopaminaen las vías mesolímbicas y mesocorticales. En estas últimas décadas se ha diseñado, sintetizado y evaluado farmacológicamentenumerosos compuestos con actividad antipsicótica, aunque la mayoría producen importantesefectos secundarios que afectan la calidad de vida del paciente. Basándonos en la información obtenida a través dela química medicinal se diseñaron los compuestos (5-7) y luego se realizó su síntesis a partir de las 1-tetralonas, conla o-iodoanilina mediante las condiciones de la reacción de sustitución nucleofílica radicalaria unimolecular (SRNI).Con el propósito de determinar su actividad antagonistica sobre los receptores dopaminérgicos en el sistema nerviosocentral, los compuestos fueron evaluados farmacológicamente mediante la administración de dosis bajas delos compuestos (100μg/5μl, 10μg/5μl y 1.0μg/5μl) por vía intracerebroventricular (ICV) a ratas, y registrando la apariciónde varias conductas estereotípicas. Los resultados biológicos muestran que los compuestos (5-7) actúan através de mecanismos dopaminérgicos, al menos a las dosis usadas, sin inducir algunos comportamientos estereotipadoscomo roer. Además son capaces de inhibir las roídas inducidas por la apomorfina. Los estudios comparativosconformacionales y electrónicos de los compuestos (4-7), a través de los cálculos cuánticos computacionales,apoyan la similitud estereoelectrónica de estos compuestos y están en concordancia con los resultados farmacológicosobtenidos