Skip to main content
SpringerLink
Log in

Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

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 is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63(1):182–217. https://doi.org/10.1124/pr.110.002642

    Article  CAS  Google Scholar 

  2. Luthra 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/10.2174/138955712803832645

    Article  CAS  Google Scholar 

  3. Poewe 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.0b013e31819908ce

  4. Seeman P, Watanabe M, Grigoriadis D (1985) Dopamine D2 receptor binding sites for agonists: a tetrahedral model. Mol Pharmacol 28(5):391–399

    CAS  Google Scholar 

  5. McDonald 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)90037-6

    Article  CAS  Google Scholar 

  6. Mottola 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/jm9502100

    Article  CAS  Google Scholar 

  7. Alkorta 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/BF00125324

    Article  CAS  Google Scholar 

  8. Cueva 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/jm0604979

    Article  CAS  Google Scholar 

  9. Negash 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/jm970157a

    Article  CAS  Google Scholar 

  10. Pettersson 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/BF01676958

    Article  CAS  Google Scholar 

  11. Tonani 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/BF01676956

    Article  CAS  Google Scholar 

  12. Mewshaw 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/jm9703653

    Article  CAS  Google Scholar 

  13. Chidester 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):1301–1315

    Article  CAS  Google Scholar 

  14. Alkorta I, Villar HO (1994) Molecular electrostatic potential of d1 and d2 dopamine agonists. J Med Chem 37(1):210–213

    Article  CAS  Google Scholar 

  15. Wilcox 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/jm9800292

    Article  CAS  Google Scholar 

  16. El 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.2009.06.033

    Article  Google Scholar 

  17. Berenguer 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.2009.05.079

    Article  CAS  Google Scholar 

  18. Andujar 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/s00894-011-1061-0

    Article  CAS  Google Scholar 

  19. Angelina 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 27:128–134

    Article  CAS  Google Scholar 

  20. Parraga 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 68:150–166

    Article  CAS  Google Scholar 

  21. Andujar 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):3233–3244

    Article  CAS  Google Scholar 

  22. Párraga 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.2016.06.009

  23. Galán 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.2013.03.042

    Article  Google Scholar 

  24. Malo 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.200900398

    Article  CAS  Google Scholar 

  25. Lan 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.105.017244

    CAS  Google Scholar 

  26. Neve 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):373–381

    CAS  Google Scholar 

  27. Kalani 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 101:3815–3820

    Article  Google Scholar 

  28. Becker 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.0401862101

    Article  CAS  Google Scholar 

  29. Micheli 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/jm0705612

    Article  CAS  Google Scholar 

  30. Párraga 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.2013.07.036

  31. Angelina 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.201400093

  32. Morris 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):2785–2791

    Article  CAS  Google Scholar 

  33. Lindorff-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.22711

    CAS  Google Scholar 

  34. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174

    Article  CAS  Google Scholar 

  35. Case 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 Francisco

    Google Scholar 

  36. Ryckaert 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)90098-5

    Article  CAS  Google Scholar 

  37. Izaguirre JA, Catarello DP, Wozniak JM, Skeel RD (2001) Langevin stabilization of molecular dynamics. J Chem Phys 114(5):2090–2098. https://doi.org/10.1063/1.1332996

    Article  CAS  Google Scholar 

  38. Essmann U, Perera L, Berkowitz M, Darden T, Lee H, Pedersen L (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593

    Article  CAS  Google Scholar 

  39. Hou 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):2982–2995

    Article  CAS  Google Scholar 

  40. Gohlke 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):891–913

    Article  CAS  Google Scholar 

  41. Frisch 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, Wallingford

  42. Bader RFW (1994) Atoms in molecules: a quantum theory. Clarendon, Oxford

  43. Lu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33(5):580–592

    Article  Google Scholar 

  44. Case 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.20290

    Article  CAS  Google Scholar 

  45. Angel 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):1934

    Google Scholar 

  46. Andujar 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/ci2004225

    Article  CAS  Google Scholar 

  47. Sealfon 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):16683–16688

    Article  CAS  Google Scholar 

  48. Trzaskowski 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/10.2174/092986712799320556

    Article  CAS  Google Scholar 

  49. Tosso 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):2018–2032

    Article  CAS  Google Scholar 

  50. Ortiz 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.5b00785

    Article  CAS  Google Scholar 

  51. Luchi 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.3586

Download references

Acknowledgements

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). The authors would like to thanks MSc. Daniel O. Zamo for technical assistance (CONICET-Argentina).

Author information

Authors and Affiliations

  1. IMIBIO-SL, CONICET, San Luis, Argentina

    Oscar Parravicini, Sebastián Rojas, Sebastián A. Andujar, Lucas J. Gutierrez & Ricardo D. Enriz

  2. IQUIBA-NEA, UNNE, CONICET, FACENA, Corrientes, Argentina

    M. Lucrecia Bogado & Emilio L. Angelina

  3. IMIBIO-SL, CONICET, FQBF, UNSL, Chacabuco 915, 5700, San Luis, Argentina

    Oscar Parravicini, Sebastián A. Andujar, Lucas J. Gutierrez & Ricardo D. Enriz

  4. Dpto de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain

    Nuria Cabedo & Diego Cortes

  5. INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain

    Nuria Cabedo & M. Jesús Sanz

  6. Dpto de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

    M. Jesús Sanz

  7. Instituto de Biología Molecular y Celular de Plantas, Universitat Politècnica de València, CSIC, Ciudad Politécnica de la Innovación, Valencia, Spain

    M. Pilar López-Gresa

Authors
  1. Oscar Parravicini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Lucrecia Bogado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sebastián Rojas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emilio L. Angelina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sebastián A. Andujar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lucas J. Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nuria Cabedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Jesús Sanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Pilar López-Gresa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Diego Cortes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ricardo D. Enriz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ricardo D. Enriz.

Additional information

This paper belongs to Topical Collection QUITEL 2016

Electronic supplementary material

ESM 1

(DOCX 948 kb)

ESM 2

(DOCX 645 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parravicini, O., Bogado, M.L., Rojas, S. et al. Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor. J Mol Model 23, 273 (2017). https://doi.org/10.1007/s00894-017-3441-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-017-3441-6

Keywords

Search

Navigation