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QSAR Study on Dual 5‐HT 1A and 5‐HT 1B Antagonists: An Insight into the Structural Requirement for Antidepressant Activity
Author(s) -
Dessalew Nigus
Publication year - 2008
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200700224
Subject(s) - autoreceptor , quantitative structure–activity relationship , chemistry , steric effects , antagonist , antagonism , 5 ht receptor , stereochemistry , serotonin , receptor , biochemistry
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‐HT 1A and 5‐HT 1B , 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 ( r 2 cv ) of 0.780 for 5‐HT 1A and 0.638 5‐HT 1B antagonism. The squared conventional correlation co‐efficients ( r 2 ) were found to be 0.824 for the 5‐HT 1A model and 0.745 for 5‐HT 1B 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.