2. Academic Validation
  3. 1,4-Disubstituted aromatic piperazines with high 5-HT2A/D2 selectivity: Quantitative structure-selectivity investigations, docking, synthesis and biological evaluation

1,4-Disubstituted aromatic piperazines with high 5-HT2A/D2 selectivity: Quantitative structure-selectivity investigations, docking, synthesis and biological evaluation

  • Bioorg Med Chem. 2015 Sep 15;23(18):6195-209. doi: 10.1016/j.bmc.2015.07.050.
Dorothee Möller 1,  Ismail Salama 2,  Ralf C Kling 1,  Harald Hübner 1,  Peter Gmeiner 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraβe 19, D-91052 Erlangen, Germany.
  • 2 Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraβe 19, D-91052 Erlangen, Germany; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suez Canal University, 41522 Ismailia, Egypt. Electronic address: [email protected].
  • 3 Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraβe 19, D-91052 Erlangen, Germany. Electronic address: [email protected].
PMID: 26299826 DOI: 10.1016/j.bmc.2015.07.050
Abstract

Simultaneous targeting of dopamine D2 and 5-HT2A receptors for the treatment of schizophrenia is one key feature of typical and atypical antipsychotics. In most of the top-selling antipsychotic drugs like aripiprazole and risperidone, high affinity to both receptors can be attributed to the presence of 1,4-disubstituted aromatic piperazines or piperidines as primary receptor recognition elements. Taking advantage of our in-house library of phenylpiperazine-derived Dopamine Receptor ligands and experimental data, we established highly significant CoMFA and CoMSIA models for the prediction of 5-HT2A over D2 selectivity. Subsequently, the models were applied to identify the selective candidates 55-57 from our newly synthesized library of GPCR ligands comprising a pyrazolo[1,5-a]pyridine head group and a 1,2,3-triazole based linker unit. The test compound 57 showed subnanomolar a Ki value (0.64 nM) for 5-HT2A and more than 10- and 30-fold selectivity over the Dopamine Receptor isoforms D2S and D2L, respectively.

Keywords

1,4-DAP; 3D-QSAR; 5-HT(2A)/D(2) selectivity; CoMFA; CoMSIA; D(2) partial agonist; Dopamine receptor; GPCR; Phenylpiperazine; Serotonin receptor; Subtype selectivity.

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