Inhibition of serotonin transporter (SERT) results in increased concentration of serotonin in the synaptic cleft. Drugs selectively inhibiting SERT have been used in many psychiatric disorders including depression, anxiety and obsessive compulsive disorder. 6-Nitroquipazine (1) is a potent SERT inhibitor with an affinity constant K_i = 0.17 nM [1] having higher affinity than clinically used inhibitors such as fluoxetine, fluvoxamine, paroxetine or sertraline [2].

Here we report the synthesis and pharmacological evaluation of a series of alkyl-nitroquipazine analogues as mixed 5-HT_1A receptor/SERT ligands. The compounds exhibited diversified 5-HT_1A receptor and SERT affinity with saw-like affinity-alkyl chain length relationship. Some of them affected SERT functioning in vitro and in vivo.

This study was partly supported by a grant PNRF-103-AI-1/07 from Norway through the Norwegian Financial Mechanism.

1. Cappelli A., Giuliani G., Gallelli A., Valenti S., Anzini M., Mennuni L., Makovec F., Cupello A., Vomero S. Structure-affinity relationship studies on arylpiperazine derivatives related to quipazine as serotonin trnasporter ligands. Molecular basis of the selectivity SERT/5HT₃ receptor. Bioorg. Med. Chem. 13, 3455-3460 (2005).
2. Lee B. S., Chu S., Lee B.-S., Chi D. Y., Chi D. Y., Song Y. S., Jin C. Synthesis and binding affinities of 6-nitroquipazine analogues for serotonin transporter. Part 2. Substituted 6-nitroquipazines. Bioorg. Med. Chem. Lett. 12  811-815 (2002). 

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