QSAR study on dual 5-HT1A and 5-HT1B antagonists: an insight into the structural requirement for antidepressant activity.
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.
Dessalew
Nigus
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Department of Pharmaceutical Chemistry, School of Pharmacy, Addis Ababa University, Addis Ababa, Ethiopia. dnigus@phar.aau.edu.et
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
D000928:Antidepressive Agents; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists