An Improved Simplified Model

Replacement of the o-methoxy group at the phenylpiperazino moiety with a chlorine atom led to comparable or slightly lower affinity, in agreement with many other experimental data reported in the literature. This result is validated by the model, showing that both the methoxy and chlorine groups interacted in a similar way with the HY1 pharmacophoric feature. 

To check the reliability of the model and to assess its predictive power, a validation step was performed by predicting affinity data for a large test set of compounds collected from three different sources, (i) Glutarimido derivatives belonging to the same class of compounds used to build the training set were evaluated against the pharmacophore model to predicting their affinity values. 

The different spatial position of the HY1-RA features (relative to the HY1-HY2 features of the first model for ald-AR antagonists) allowed a better prediction of affinity values for compounds bearing a para substituent at the phenyl ring attached to the piperazine nucleus. 

All these facts lead to the conclusion that our new five-feature pharmacophore model should be a good abstract representation of the most important structural elements that a compound should possess for high a1(j adrenoceptor affinity. Similarity between the HBA and PI features of the pharmacophore model with parts of the theoretical receptor could be also considered as an additional validation of our model. 

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