| Abstract
| - The molecular alignments obtained from a previously reported pharmacophore model have been employedin a three-dimensional quantitative structure−activity relationship (3D QSAR) study, to obtain a more detailedinsight into the structure−activity relationships for D2 and D4 receptor antagonists. The frequently appliedCoMFA method and the related CoMSIA method were used. Statistically significant models have beenderived 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. Thepredictive 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 toeither low- or high-affinity D2 or D4 antagonism. The results of the 3D QSAR studies indicate that bulkyN-substituents decrease D2 binding, whereas D4 binding is enhanced. Electrostatically favorable andunfavorable regions exclusive to D2 receptor binding were identified. Likewise, certain hydrogen-bondacceptors can be used to lower D2 affinity. These observations may be exploited for the design of noveldopamine D4 selective antagonists.
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