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Abstract
Selective human serotonin reuptake transporter (hSERT) inhibition is the first line of treatment to deal with the depression. In clinical practice for managing depression, the stimulants are co-prescribed to overcome cognitive impairment and fatigue. Recently, histamine H3 antagonists with serotonin reuptake inhibition activity have been proposed as alternative approach for the treatment of depression. In this context, a QSAR study of hSERT inhibitory and H3 antagonistic activity of piperazine and diazepane amide derivatives has been carried out using the combinatorial protocol in multiple linear regression (CP-MLR) with 0D- to 2D-Dragon descriptors. The derived QSAR models have provided a rational approach for the development of new piperazine and diazepane amide derivatives as hSERT inhibitors and H3 antagonists. In a concomitant partial least-squares (PLS) analysis of the hSERT and histamine H3 activities, the fraction contributions of identified descriptors revealed their importance in modulating these activities. The PLS analysis of other biological endpoints, namely hNET, hDAT, and histamine H3 activity in functional assay (H3pA2) of these analogues with the identified descriptors has further highlighted their scope in modulating these activities.
Acknowledgements
Authors express their sincere gratitude to their Institutions for providing necessary facilities to complete this study. KS thanks UGC, Bhopal India for financial support in the form of TRF. CDRI communication number 8003.
Supporting information
The complete dataset of molecular descriptors of structure database of , loadings, PLS weights and sensitivity of independent and dependent descriptors of the PLS models is available via the Supplementary Content tab on the article's online page at http://dx.doi.org/10.1080/1062936X.2011.569895.