title: 1,4-Disubstituted aromatic piperazines with high 5-HT2A/D2 selectivity: Quantitative structure-selectivity investigations, docking, synthesis and biological evaluation.
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.
authors: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraβe 19, D-91052 Erlangen, Germany.
authors: Dorothee
authors: D
authors: Möller
authors: 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: ismail_mohamed@pharm.suez.edu.eg.
authors: Ismail
authors: I
authors: Salama
authors: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraβe 19, D-91052 Erlangen, Germany.
authors: Ralf C
authors: RC
authors: Kling
authors: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraβe 19, D-91052 Erlangen, Germany.
authors: Harald
authors: H
authors: Hübner
authors: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraβe 19, D-91052 Erlangen, Germany. Electronic address: peter.gmeiner@fau.de.
authors: Peter
authors: P
authors: Gmeiner
mesh_terms: D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2
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