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

Abstract

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.

Keywords

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)
11064_2014_1314_MOESM2_ESM.zip (64 kb)
Supplementary material 2 (.zip 64 kb)
11064_2014_1314_MOESM3_ESM.zip (8 kb)
Supplementary material 3 (.zip 9 kb)
11064_2014_1314_MOESM4_ESM.pdf (593 kb)
Supplementary material 4 (PDF 594 kb)

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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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