During our work concerning new antidepressive drugs we obtained several serotonin transporter inhibitors of nanomolal affinity [1]. During behavioural experiments on mice some of the compounds exhibited moderate activity at the force swim test and induced hypothermia. Similar behavioural profile exhibit citalopram, clinically used serotonin selective reuptake inhibitor (SSRI, it is assumed that hypothermia as a part of serotonergic syndrome is conveyed by the 5-HT_1A and 5-HT_1B receptors) [2]. One of our compounds (AZ-07) although did not evoke hypothermia, amplified substantially 8-OHDPAT (the referenced 5-HT_1A receptor agonist) induced hypothermia. It should be noted that another SSRI, fluoxetine, reversed 8-OHDPAT induced hypothermia [3]. Because our compounds did not exhibit any substantial 5-HT_1A receptor affinity one could assumed off-target of allosteric effects.

References:

[1]  Jarończyk M., Wołosewicz K., Gabrielsen M., Nowak G., Kufareva I., Mazurek A. P., Ravna A. W., Abagyan R., Bojarski A. J., Sylte I., Chilmonczyk Z.: Synthesis, in vitro binding studies and docking of long-chain arylpiperazine nitroquipazine analogues, as potential serotonin transporter inhibitors. Eur. J. Med. Chem. 49, 200-210 (2012). 

[2] Oerther S., Ahlenuis S.: Involvement of 5-HT1A and 5-HT1B receptors for citalopram-induced hypothermia in the rat. Psychopharmacol. 154, 429-434 (2001).

[3]  Nguyen H.T., Quesseveur G., Gardier A.M., David D.J., Guiard B.P.: Functional status of somatodendritic serotonin 1A autoreceptor after long-term treatment with fluoxetine in a mouse model of anxiety/depression based on repeated corticortesterone administration. Mol. Pharmacol. 81, 106-112 (2012).

The project was partially supported by the Polish Norwegian Research Program grant Pol-Nor/198887/73/2013

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