Modelling of serotonin reuptake inhibitory and histamine H₃ antagonistic activity of piperazine and diazepane amides: QSAR rationales for co-optimization of the activity profiles

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.

Keywords:

• combinatorial protocol in multiple linear regression (CP-MLR)
• human dopamine transporter (hDAT)
• human histamine₃ (hH₃)
• human norepinephrine transporter (hNET)
• human serotonin reuptake transporter (hSERT)
• PLS analysis
• rat serotonin reuptake transporter (rSERT)

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 Table 1, 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.