title: A 3D QSAR study on a set of dopamine D4 receptor antagonists.
abstract: The molecular alignments obtained from a previously reported pharmacophore model have been employed in a three-dimensional quantitative structure-activity relationship (3D QSAR) study, to obtain a more detailed insight into the structure-activity relationships for D(2) and D(4) receptor antagonists. The frequently applied CoMFA method and the related CoMSIA method were used. Statistically significant models have been derived with these two methods, based on a set of 32 structurally diverse D(2) and D(4) receptor antagonists. The CoMSIA and the CoMFA methods produced equally good models expressed in terms of q(2) values. The predictive power of the derived models were demonstrated to be high. Graphical interpretation of the results, provided by the CoMSIA method, brings to light important structural features of the compounds related to either low- or high-affinity D(2) or D(4) antagonism. The results of the 3D QSAR studies indicate that bulky N-substituents decrease D(2) binding, whereas D(4) binding is enhanced. Electrostatically favorable and unfavorable regions exclusive to D(2) receptor binding were identified. Likewise, certain hydrogen-bond acceptors can be used to lower D(2) affinity. These observations may be exploited for the design of novel dopamine D(4) selective antagonists.
authors.affiliation: H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen-Valby, Denmark. jonas.bostrom@astrazeneca.com
authors.forename: Jonas
authors.initials: J
authors.lastname: Boström
authors.forename: Markus
authors.initials: M
authors.lastname: Böhm
authors.forename: Klaus
authors.initials: K
authors.lastname: Gundertofte
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
mesh_terms: D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D050638:Receptors, Dopamine D4; D055672:Static Electricity
chemical_list: C493599:DRD4 protein, human; D065127:Dopamine D2 Receptor Antagonists; D050638:Receptors, Dopamine D4