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A 3D QSAR Study on a Set of Dopamine D4 Receptor Antagonists

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posted on 02.05.2003, 00:00 by Jonas Boström, Markus Böhm, Klaus Gundertofte, Gerhard Klebe
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 D2 and D4 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 D2 and D4 receptor antagonists. The CoMSIA and the CoMFA methods produced equally good models expressed in terms of q2 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 D2 or D4 antagonism. The results of the 3D QSAR studies indicate that bulky N-substituents decrease D2 binding, whereas D4 binding is enhanced. Electrostatically favorable and unfavorable regions exclusive to D2 receptor binding were identified. Likewise, certain hydrogen-bond acceptors can be used to lower D2 affinity. These observations may be exploited for the design of novel dopamine D4 selective antagonists.