Neurochemical Research

, Volume 39, Issue 10, pp 1997–2007 | Cite as

Revision of the Classical Dopamine D2 Agonist Pharmacophore Based on an Integrated Medicinal Chemistry, Homology Modelling and Computational Docking Approach

  • N. Krogsgaard-Larsen
  • K. Harpsøe
  • J. Kehler
  • C. T. Christoffersen
  • P. Brøsen
  • T. Balle
Original Paper


The scientific advances during the 1970ies and 1980ies within the field of dopaminergic neurotransmission enabled the development of a pharmacophore that became the template for design and synthesis of dopamine D2 agonists during the following four decades. A major drawback, however, is that this model fails to accommodate certain classes of restrained dopamine D2 agonists including ergoline structures. To accommodate these, a revision of the original model was required. The present study has addressed this by an extension of the original model without compromising its obvious qualities. The revised pharmacophore contains an additional hydrogen bond donor feature, which is required for it to accommodate ergoline structures in a low energy conformation and in accordance with the steric restrictions dictated by the original model. The additional pharmacophore feature suggests ambiguity in the binding mode for certain compounds, including a series of ergoline analogues, which was reported recently. The ambiguity was confirmed by docking to a homology model of the D2 receptor as well as by pharmacological characterization of individual enantiomers of one of the analogues. The present research also addresses the potential of designing ligands that interact with the receptor in a large, distal cavity of the dopamine D2 receptor that has not previously been studied systematically. The pharmacological data indicate that this area may be a major determinant for both the dopamine D2 affinity and efficacy, which remains to be explored in future studies.


Dopamine D2 agonist pharmacophore Dopamine D2 receptor Dopamine D2 agonist Homology modelling GPCR docking Ergoline derivative Dopamine D2 SAR 

Supplementary material

11064_2014_1314_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 16 kb) (64 kb)
Supplementary material 2 (.zip 64 kb) (8 kb)
Supplementary material 3 (.zip 9 kb)
11064_2014_1314_MOESM4_ESM.pdf (593 kb)
Supplementary material 4 (PDF 594 kb)


  1. 1.
    Beaulieu J-M, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63:182–217PubMedCrossRefGoogle Scholar
  2. 2.
    Ehringer H, Hornykiewicz O (1960) Distribution of noradrenaline and dopamine (3-Hydroxytryamine) in the human brain and their behavior in diseases of the extrapyramidal system. Klin. Wochenschr. 38:1236–1239PubMedCrossRefGoogle Scholar
  3. 3.
    Snyder SH, Taylor KM, Coyle JT, Meyerhoff JL (1970) The role of brain dopamine in behavioral regulation and the actions of psychotropic drugs. Am J Psychiatry 127:199–207PubMedGoogle Scholar
  4. 4.
    Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483PubMedCrossRefGoogle Scholar
  5. 5.
    Seeman P, Lee T, Chau-Wong M, Wong K (1976) Antipsycotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–719PubMedCrossRefGoogle Scholar
  6. 6.
    Carlsson A (2001) A paradigm shift in brain research. Science 294:1021–1024PubMedCrossRefGoogle Scholar
  7. 7.
    Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225PubMedGoogle Scholar
  8. 8.
    Iversen SD, Iversen LL (2007) Dopamine: 50 years in perspective. Trends Neurosci 30:188–193PubMedCrossRefGoogle Scholar
  9. 9.
    Swanson JM, Kinsbourne M, Nigg J, Lanphear B, Stefanatos GA, Volkow N, Taylor E, Casey BJ, Castellanos FX, Wadhwa PD (2007) Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol Rev 17:39–59PubMedCrossRefGoogle Scholar
  10. 10.
    Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126:51–90PubMedCrossRefGoogle Scholar
  11. 11.
    Mink JW (2006) Neurobiology of basal ganglia and tourette syndrome: basal ganglia circuits and thalamocortical outputs. Adv Neurol 99:89–98PubMedGoogle Scholar
  12. 12.
    Jakel RJ, Maragos WF (2000) Neuronal cell death in huntington’s disease: a potential role for dopamine. Trends Neurosci 23:239–245PubMedCrossRefGoogle Scholar
  13. 13.
    Cyr M, Sotnikova TD, Gainetdinov RR, Caron MG (2006) Dopamine enhances motor and neuropathological consequences of polyglutamine expanded Huntingtin. Faseb J 20:2541–2543PubMedCrossRefGoogle Scholar
  14. 14.
    Strange PG (1992) Brain biochemistry and brain disorders. Oxford University Press, OxfordGoogle Scholar
  15. 15.
    Cools AR, Van Rossum JM (1976) Exicitation-mediating and inhibition-mediating dopamine-receptors: a new concept towards a better understanding of electrophysiological, biochemical, pharmacological, functional and clinical data. Psychopharmacologia 45:243–254PubMedCrossRefGoogle Scholar
  16. 16.
    Spano PF, Govoni S, Trabucchi M (1978) Studies on the pharmacological properties of dopamine receptors in various areas of the central nervous system. Adv Biochem Psychopharmacol 19:155–165PubMedGoogle Scholar
  17. 17.
    Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277:93–96PubMedCrossRefGoogle Scholar
  18. 18.
    Sibley DR, Monsma FJ (1992) Molecular biology of dopamine receptors. Trends Pharmacol Sci 13:61–69PubMedCrossRefGoogle Scholar
  19. 19.
    Jarvie KR, Caron MG (1993) Heterogeneity of dopamine receptors. Adv Neurol 60:325–333PubMedGoogle Scholar
  20. 20.
    Strange PG (1996) Dopamine receptors: studies on their structure and function. Adv Drug Res 28:315–319Google Scholar
  21. 21.
    Sokoloff P, Giros B, Martres MP, Barthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D-3) as a target for neuroleptics. Nature 347:146–151PubMedCrossRefGoogle Scholar
  22. 22.
    Van Tol HHM, Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614PubMedCrossRefGoogle Scholar
  23. 23.
    Sunahara RK, Guan HC, O’Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HHM, Niznik HB (1991) Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature 350:614–619PubMedCrossRefGoogle Scholar
  24. 24.
    Brown DA, Kharkar PS, Parrington I, Reith MEA, Dutta AK (2008) Structurally constrained hybrid derivatives containing octahydrobenzo [g or f] quinolone moieties for dopamine D2 and D3 receptors: binding characterisation at D2/D3 receptors and elucidation of a pharmacophore model. J Med Chem 51:7806–7819PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    McDermed JD, McKenzie GM, Freeman HS (1976) Synthesis and dopaminergic activity of (±)-, (+)-, and (−)-2-dipropylamino-5-hydroxy-1,2,3,4-tetrahydronaphthalene. J Med Chem 19:547–549PubMedCrossRefGoogle Scholar
  26. 26.
    Tedesco JL, Seeman P, McDermed JD (1979) The conformation of dopamine at its receptor: binding of monohydroxy-2-aminotetralin enantiomers and positional isomers. Mol Pharmacol 16:369–381PubMedGoogle Scholar
  27. 27.
    Cannon JG, Lee T, Goldman HD, Costall B, Naylor RJ (1977) Cerebral dopamine agonist properties of some 2-aminotetralin derivatives after peripheral and intracerebral administration. J Med Chem 20:1111–1116PubMedCrossRefGoogle Scholar
  28. 28.
    McDermed JD, McKenzie GM, Phillips AP (1975) Synthesis and pharmacology of some 2-aminotetralins. Dopamine receptor agonists. J Med Chem 18:362–367PubMedCrossRefGoogle Scholar
  29. 29.
    Hacksell U, Svensson U, Nilsson JLG, Hjorth S, Carlsson A, Wikström H, Lindberg P, Sanchez D (1979) N-alkylated 2-aminotetralins: central dopamine-receptor stimulating activity. J Med Chem 22:1469–1475PubMedCrossRefGoogle Scholar
  30. 30.
    Caprathe BW, Jaen JC, Wise LD, Heffner TG, Pugsley TA, Meltzer LT, Pervez M (1991) Dopamine autoreceptor agonists as potential antipsychotics. 3. 6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo [4,5-f]quinolin-2-amine. J Med Chem 34:2736–2746PubMedCrossRefGoogle Scholar
  31. 31.
    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, Mazandarani 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 40:4235–4256PubMedCrossRefGoogle Scholar
  32. 32.
    Mewshaw RE, Verwijs A, Shi X, McGaughey GB, Nelson JA, Mazandarani H, Brennan JA, Marquis KL, Coupet J, Andree TH (1998) New generation dopaminergic agents. 5. Heterocyclic bioisosters that exploit the 3-OH-N1-Phenypiperazine dopaminergic template. Bioorg Med Chem Lett 8:2675–2680PubMedCrossRefGoogle Scholar
  33. 33.
    Jain ZJ, Kankate RS, Chaudhari BN, Kakad RD (2013) Action of benzimidazolo-piperazinyl derivatives on dopamine receptors. Med Chem Res 22:520–530CrossRefGoogle Scholar
  34. 34.
    Wikström H, Liljefors T (1986) A molecular mechanics approach to the understanding of presynaptic selectivity for centrally acting dopamine receptor agonists of the phenylpiperidine series. J Med Chem 29:1896–1904PubMedCrossRefGoogle Scholar
  35. 35.
    Liljefors T, Bøgesø KP, Hyttel J, Wikström H, Svensson K, Carlsson A (1990) Pre- and postsynaptic dopaminergic activities of indolizidine and quinolizidine derivatives of 3-(3-Hydroxyphenyl)-N-(n-propyl)piperidine (3-PPP). further developments of a dopamine receptor model. J Med Chem 33:1015–1022PubMedCrossRefGoogle Scholar
  36. 36.
    Sanjib G, Biswas S, Modi G, Antonio T, Reith MEA, Dutta AK (2012) Novel bivalent ligands for D2/D3 dopamine receptors: significant cooperative gain in D2 affinity and potency. Med Chem Lett 3:991–996CrossRefGoogle Scholar
  37. 37.
    Audinot V, Newman-Tancredi A, Gobert A, Rivet J-M, Brocco M, Lejeune F, Gluck L, Desposte I, Bervoets K, Dekeyne A, Millan MJ (1998) A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, Nafadotride, GR 103,691 and U 99194. J Pharmacol Exp Ther 287:187–197PubMedGoogle Scholar
  38. 38.
    Wikström H, Anderson B, Elebring T, Svensson K, Carlsson A, Largent B (1987) N-substituted 1,2,3,4,4a,5,6,10b-Octahydrobenzo[f]quinolones and 3-phenylpiperidines: effects on central dopamine and a receptors. J Med Chem 30:2169–2174PubMedCrossRefGoogle Scholar
  39. 39.
    Martin GE, Williams M, Pettibone DJ, Yarbrough GG, Clineschmidt BV, Jones JH (1984) Pharmacological profile of a novel potent direct-acting dopamine agonist, (+)-4-Propyl-9-hydroxynaphthoxazine [(+)-PHNO]. J Pharmacol Exp Ther 230:569–576PubMedGoogle Scholar
  40. 40.
    Heier RF, Dolak LA, Duncan JN, Hyslop DK, Lipton MF, Martin IJ, Mauragis MA, Piercey MF, Nichols NF, Schreur PJKD, Smith MW, Moon MW (1997) Synthesis and biological activities of (R)-5,6-Dihydro-N, N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites. J Med Chem 40:639–646PubMedCrossRefGoogle Scholar
  41. 41.
    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 5:232–246PubMedCrossRefGoogle Scholar
  42. 42.
    Bøgesø KP, Arnt J, Lundmark M, Sundell S (1987) Indolizidine and quinolizidine derivatives of the dopamine autoreceptor agonist 3-(3-Hydroxyphenyl)-N-n-propylpiperidine (3-PPP). J Med Chem 30:142–150PubMedCrossRefGoogle Scholar
  43. 43.
    Larson BT, Harmon DL, Piper EL, Griffis LM, Bush LP (1999) Alkaloid binding and activation of D2 dopamine receptors in cell culture. J Anim Sci 77:942–947PubMedGoogle Scholar
  44. 44.
    Herm L, Berényi S, Vonk A, Rinken A, Sipos A (2009) N-substituted-2-alkyl- and 2-arylnorapomorphines: novel, highly active D2 agonists. Bioorg Med Chem 17:4756–4762PubMedCrossRefGoogle Scholar
  45. 45.
    Mottola DM, Brewster WK, Cook LL, Nichols DE, Mailman RB (1992) Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist. J Pharmacol Exp Ther 262:383–393PubMedGoogle Scholar
  46. 46.
    Novi F, Millan MJ, Corsini GU, Maggio R (2007) Partial agonist actions of aripiprazole and the candidate antipsychotics S33592, bifeprunox, N-desmethylclozapine and preclamol at dopamine D2L receptors are modified by co-transfection of D3 receptors: potential role of heterodimer formation. J Neurochem 102:1410–1424PubMedCrossRefGoogle Scholar
  47. 47.
    Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, Millan MJ (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor. J Pharmacol Exp Ther 303:805–814PubMedCrossRefGoogle Scholar
  48. 48.
    Cosi C, Carilla-Durand E, Assié MB, Ormiere AM, Maraval M, Leduc N, Newman-Tancredi A (2006) Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release. Eur J Pharmacol 535:135–144PubMedCrossRefGoogle Scholar
  49. 49.
    Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang X-P, Vardy E, McCorvy JD, Gao X, Zhou E, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, Xu HE (2013) Structural basis for molecular recognition at serotonin receptors. Science 340:610–614PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330:1091–1095PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    The PyMOL Molecular Graphics System, Version 1.5.0, Schrödinger LLC, New York, NY, 2013Google Scholar
  52. 52.
    Krogsgaard-Larsen N, Begtrup M, Frydenvang K, Kehler J (2010) Syntheses of aza-analogous iso-ergoline scaffolds using carbene mediated C-H insertion. Tetrahedron 66:9297–9303CrossRefGoogle Scholar
  53. 53.
    Krogsgaard-Larsen N, Jensen AA, Schrøder TJ, Christoffersen CT, Kehler J (2014) Novel aza-analogous ergoline derived scaffolds as potent serotonin 5-HT6 and dopamine D2 receptor ligands. J Med Chem. doi:10.1021/jm5003759
  54. 54.
    Wheatley M, Wootten D, Conner MT, Simms J, Kendrick R, Logan RT, Poyner DR, Barwell J (2012) Lifting the lid on GPCRs: the role of extracellular loops. Br J Pharmacol 165:1688–1703PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Ring AM, Manglik A, Kruse AC, Enos MD, Weis WI, Garcia KC, Kobilkal BK (2013) Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody. Nature 502:575–579PubMedCrossRefGoogle Scholar
  56. 56.
    Rasmussen SGF, Choi H-J, Fung JJ, Pardon E, Casarosa P, Chae PS, DeVree BT, Rosenbaum DM, Thian FS, Kobilka TS, Schnapp A, Konetzki I, Sunahara RK, Gellamn SH, Pautsch A, Steyaert J, Weis WI, Kobilka BK (2011) Structure of a nanobody-stabilized active state of the β2 adrenoceptor. Nature 469:175–180PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    UniProt Consortium (2010) Ongoing and future developments at the universal protein resource. Nucleic Acids Res 39:D214–D219CrossRefGoogle Scholar
  58. 58.
    Ballesteros J, Weinstein H (1995) Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein coupled receptors. Methods Neurosci 25:366–428CrossRefGoogle Scholar
  59. 59.
    Maestro, version 9.6, Schrödinger, LLC, New York, NY, 2013Google Scholar
  60. 60.
    MacroModel, version 10.2, Schrödinger, LLC, New York, NY, 2013Google Scholar
  61. 61.
    Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815PubMedCrossRefGoogle Scholar
  62. 62.
    Berman HM, Weatbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948PubMedCrossRefGoogle Scholar
  64. 64.
    Tfelt-Hansen P, Saxena PR, Dahlöf C, Pascual J, Láinez M, Henry P, Diener H, Schoenen J, Ferrari MD, Goadsby PJ (2000) Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 123:9–18PubMedCrossRefGoogle Scholar
  65. 65.
    Protein Preparation Wizard 2013-3, Schrödinger, LLC, New York, NY, 2013; Epik version 2.4; Impact version 5.9; Prime version 3.2Google Scholar
  66. 66.
    Glide, version 6.1, Schrödinger, LLC, New York, NY, 2013Google Scholar
  67. 67.
    Boström J, Norrby PO, Liljefors T (1998) Conformational energy penalties of protein-bound ligands. J Comput Aided Mol Des 12:383–396Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • N. Krogsgaard-Larsen
    • 1
  • K. Harpsøe
    • 1
    • 2
  • J. Kehler
    • 3
  • C. T. Christoffersen
    • 3
  • P. Brøsen
    • 3
  • T. Balle
    • 4
  1. 1.Department of Drug Design and Pharmacology, The Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  2. 2.The Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.H. Lundbeck A/S, Discovery Chemistry & DMPKValbyDenmark
  4. 4.Faculty of PharmacyThe University of SydneySydneyAustralia

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