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

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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.

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Acknowledgments

The chemistry described was conducted at H. Lundbeck A/S. We gratefully acknowledge the research facilities and materials provided by H. Lundbeck A/S and Department of Drug Design and Pharmacology, The Faculty of Health and Medical Sciences, The University of Copenhagen. Niels Krogsgaard-Larsen was supported by a DRA PhD scholarship provided by the Faculty of Health and Medical Sciences, The University of Copenhagen in collaboration with H. Lundbeck A/S.

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The Authors declare no competing financial interest.

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Authors and Affiliations

  1. Department of Drug Design and Pharmacology, The Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100, Copenhagen, Denmark

    N. Krogsgaard-Larsen & K. Harpsøe

  2. The Novo Nordisk Foundation Centre for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b, 2100, Copenhagen, Denmark

    K. Harpsøe

  3. H. Lundbeck A/S, Discovery Chemistry & DMPK, 9 Ottiliavej, 2500, Valby, Denmark

    J. Kehler, C. T. Christoffersen & P. Brøsen

  4. Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia

    T. Balle

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  1. N. Krogsgaard-Larsen
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  4. C. T. Christoffersen
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Correspondence to T. Balle.

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Special Issue: In honor of Krogsgaard-Larsen.

N. Krogsgaard-Larsen and K. Harpsøe have contributed equally to this article.

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Krogsgaard-Larsen, N., Harpsøe, K., Kehler, J. et al. Revision of the Classical Dopamine D2 Agonist Pharmacophore Based on an Integrated Medicinal Chemistry, Homology Modelling and Computational Docking Approach. Neurochem Res 39, 1997–2007 (2014). https://doi.org/10.1007/s11064-014-1314-2

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