QSAR Study on Dual 5‐HT1A and 5‐HT1B Antagonists: An Insight into the Structural Requirement for Antidepressant Activity
Nigus Dessalew · Archiv der Pharmazie · 2008
The 5-HT autoreceptors have received considerable attention as potential targets for the development of antidepressants. With the purpose of designing new chemical entities with enhanced antagonist potencies against 5-HT1A and 5-HT1B, a QSAR study carried out on thienopyrimidinone derivatives as antagonists of serotonin autoreceptors is presented. The developed models were validated by standard QSAR parameters and through a detailed structural analysis on how the QSARs reproduce and explain the differences in the experimentally known activity data. The developed models showed a good correlative and predictive ability having a squared cross validated correlation co-efficients (r2 cv) of 0.780 for 5-HT1A and 0.638 5-HT1B antagonism. The squared conventional correlation co-efficients (r2) were found to be 0.824 for the 5-HT1A model and 0.745 for 5-HT1B antagonism. The study indicated that the 5-HT autoreceptor antagonistic activity exhibited by the series is largely explained by steric factors of substituents which underline the role of size and shape of thienopyrimidinones in making effective antagonist-autoreceptor interaction chemistry. A detailed comparative investigation was made between the two models and the insights gleaned from the study could be usefully employed to design dual antagonists with a much more enhanced potency and selectivity.