Modeling 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 the depression, the stimulants are co-prescribed to overcome the 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 backdrop, 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 regressions (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 PLS analysis of the hSERT and histamine H3 activities, the fraction contributions of identified descriptors revealed their importance in modulating the 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 the activities.