Revision of the Classical Dopamine D^sub 2^ Agonist Pharmacophore Based on an Integrated Medicinal Chemistry, Homology Modelling and Computational Docking Approach

Issue Title: Special Issue in Honor of Povl Krogsgaard-Larsen 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 D^sub 2^ agonists during the following four decades. A major drawback, however, is that this model fails to accommodate certain classes of restrained dopamine D^sub 2^ 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 D^sub 2^ 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 D^sub 2^ receptor that has not previously been studied systematically. The pharmacological data indicate that this area may be a major determinant for both the dopamine D^sub 2^ affinity and efficacy, which remains to be explored in future studies.[PUBLICATION ABSTRACT]