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Synthesis, 5-HT1A and 5-HT2A receptor affinity and QSAR study of 1-benzhydryl-piperazine derivatives with xanthine moiety at N4

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Abstract

Three novel 1-benzhydryl-piperazines with xanthine moiety at N4 were synthesized and tested for 5-HT1A and 5-HT2A receptor affinity. One of the compounds showed the highest affinity (58.6 nM) and selectivity (34 times) to 5-HT2A receptor known for this class of compounds. A set of the three new and 31 previously synthesized 1-arylpiperazines with xanthine moiety at N4 was compiled and a QSAR study was performed in order to rationalize the further synthesis. It was found that the 5-HT1A affinity depends on the shape of the molecules (ovality and number of circuits), the distribution of the electron density in the structures (partial charges at piperazine N1 and xanthine N1) and their charge transfer ability (HOMO energy). The 5-HT2A affinity depends on the lipophilicity of the ligands and the distribution of the electron density in the structures (partial charges at piperazine N4 and xanthine O6). The QSAR results are in a good agreement with known pharmacophore models.

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Acknowledgments

This work was supported by grant from the Medical Science Council of the Medical University of Sofia (project 5-I/2009).

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Authors and Affiliations

  1. Faculty of Pharmacy, Medical University of Sofia, 2 Dunav st, 1000, Sofia, Bulgaria

    Iva Valkova, Alexander Zlatkov & Irini Doytchinova

  2. Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St, 31-343, Kraków, Poland

    Krystyna Nędza

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  1. Iva Valkova
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  2. Alexander Zlatkov
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  3. Krystyna Nędza
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  4. Irini Doytchinova
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Correspondence to Irini Doytchinova.

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Valkova, I., Zlatkov, A., Nędza, K. et al. Synthesis, 5-HT1A and 5-HT2A receptor affinity and QSAR study of 1-benzhydryl-piperazine derivatives with xanthine moiety at N4. Med Chem Res 21, 477–486 (2012). https://doi.org/10.1007/s00044-011-9555-y

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  • DOI: https://doi.org/10.1007/s00044-011-9555-y

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