Synthesis, antidepressant evaluation and docking studies of long-chain alkylnitroquipazines as serotonin transporter inhibitors

Abstract

Twelve alkyl analogues (1-12) of the high-affinity serotonin transporter (SERT) inhibitor 6-nitroquipazine (6-NQ) were synthesized and studied using in vitro radioligand competition binding assays to determine their binding affinity (Ki). The putative antidepressant activity of five of the binders with the highest SERT binding affinities was studied by the forced swim and locomotor activity mouse tests. The three-dimensional (3D) structures of 8 and 9 were determined using NOE NMR technique. Flexible docking of the compounds was undertaken to illustrate the binding of the compounds in the SERT model. Our results showed that several of the 6-NQ analogues are high-affinity SERT inhibitors and indicated that the octyl (8), decyl (10) and dodecyl (12) 6-NQ analogues exhibit moderate antidepressant activity. Twelve alkyl analogues 6-nitroquipazine (6-NQ) were synthesised and tested for their binding to the serotonin transporter protein (SERT) using in vitro radioligand competition binding assays and molecular docking. The putative antidepressant activity of the binders with the highest SERT binding affinities was also studied by the forced swim and locomotor activity mouse tests. The results showed that several of the 6-NQ analogues are high-affinity SERT inhibitors and that three of the analogues have moderate antidepressant activity. © 2013 John Wiley & Sons A/S.