The role of 5-HT_1A and 5-HT_2A receptors in the pathogenesis of neuropsychiatric disorders is well known. However the most recently identified serotonin receptor subtypes: 5-HT₆ and 5-HT₇ are also reported to have importance in the control of many CNS functions (thermoregulation, circadian rhythms) and dysfunction like migraine, epilepsy and depression [1]. It has been postulated that 5-HT₆ ligands may afford useful therapies for the treatment of obesity, as well as cognitive enhancement in schizophrenia and Alzheimer's disease [2].

    In the field of serotonergics we have concentrated on the development of long-chain arylpiperazines (LCPs) theophylline derivatives which were active at 5-HT_1A, 5-HT_2A and 5-HT₇ receptors [3, 4]. Among them the 8-alkoxy derivatives of 1,3-dimethyl-7- (4-ary- lpiperazinylalkyl)-3,7-dihydropurine-2,6-dione proved to be potent ligands for these receptors and showed anxiolytic and antidepressant activities in vivo models [4]. To continue our research and extend the study on 5-HT₆ receptors we designed and synthesized series of the new analogues by modification of the substituent in position 8 of the purine-2,6-dione core. Additionally the p-fluoro substituent was introduced into the phenyl ring.

    The new analogues are under evaluation for their affinity to the 5-HT₇ and 5-HT₆ receptors. The structure-activity relationship (SAR) will be discussed.

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

References:

[1] Hedlund P.B., Sutcliffe J.G.: Trends Pharmacol. Sci., 2004, 25, 481.

[2] Singer J.M. et al. Bioorg. Med. Chem. Lett., 2009, 19, 2409.

[3] Chłoń G., Pawłowski M., Duszyńska B., Szaro A., Tatarczyńska E., Kłodzińska A., Chojnacka-Wójcik E.: Pol. J. Pharmacol., 2001, 53, 359.

[4] Chłoń-Rzepa G., Żmudzki P., Zajdel P., Bojarski A.J., Duszyńska B., Nikiforuk A., Tatarczyńska E., Pawłowski M.: Bioorg. Med. Chem., 2007, 15, 5239.

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