Discovery of novel arylpiperazine-based DA/5-HT modulators as potential antipsychotic agents-Design, synthesis, structural studies and pharmacological profiling

被引：3

作者：

Stepnicki, Piotr ^{[1
]}

Targowska-Duda, Katarzyna M. ^{[2
]}

Martinez, Anton L. ^{[3
,4
]}

Zieba, Agata ^{[1
]}

Wronikowska-Denysiuk, Olga ^{[5
]}

Wrobel, Martyna Z. ^{[6
]}

Bartyzel, Agata ^{[7
]}

Trzpil, Alicja ^{[8
]}

Wrobel, Tomasz M. ^{[1
]}

Chodkowski, Andrzej ^{[6
]}

Mirecka, Karolina ^{[6
]}

Karcz, Tadeusz ^{[9
]}

Szczepanska, Katarzyna ^{[9
]}

Loza, Maria I. ^{[3
,4
]}

Budzynska, Barbara ^{[5
]}

Turlo, Jadwiga ^{[6
]}

Handzlik, Jadwiga ^{[9
]}

Fornal, Emilia ^{[8
]}

Poleszak, Ewa ^{[10
]}

Castro, Marian ^{[3
,4
]}

Kaczor, Agnieszka A. ^{[1
,11
,12
]}

机构：

[1] Med Univ Lublin, Fac Pharm, Dept Synth & Chem Technol Pharmaceut Subst, Comp Modeling Lab, 4A Chodzki St, PL-20093 Lublin, Poland

[2] Med Univ Lublin, Fac Pharm, Dept Biopharm, 4A Chodzki St, PL-20093 Lublin, Poland

[3] Univ Santiago De Compostela, Ctr Res Mol Med & Chron Dis CIMUS, Dept Pharmacol, Avda Barcelona, E-15782 Santiago De Compostela, Spain

[4] Inst Invest Sanit Santiago De Compostela IDIS, Travesia Choupana S-N, E-15706 Santiago De Compostela, Spain

[5] Med Univ Lublin, Fac Biomed, Independent Lab Behav Studies, Biomed Sci, 4A Chodzki St, PL-20093 Lublin, Poland

[6] Med Univ Warsaw, Fac Pharm, Dept Drug Technol & Pharmaceut Biotechnol, 1 Banacha St, PL-02097 Warsaw, Poland

[7] Maria Curie Sklodowska Univ Lublin, Inst Chem Sci, Fac Chem, Dept Gen & Coordinat Chem & Crystallog, Maria Curie Sklodowska Sq 2, PL-20031 Lublin, Poland

[8] Med Univ Lublin, Fac Biomed, Dept Bioanalyt Dietet & Bioanalyt, Jaczewskiego 8b St, PL-20090 Lublin, Poland

[9] Jagiellonian Univ, Med Coll, Fac Pharm, Dept Technol & Biotechnol Drugs, Med 9, PL-30688 Krakow, Poland

[10] Med Univ Lublin, Fac Pharm, Dept Appl & Social Pharm, 1 Chodzki St, PL-20093 Lublin, Poland

[11] Univ Eastern Finland, Sch Pharm, POB 1627, FI-70211 Kuopio, Finland

[12] Med Univ Lublin, Fac Pharm, Dept Synth & Chem Technol Pharmaceut Subst, 4A Chodzki St, PL-20093 Lublin, Poland

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 252卷

关键词：

Antipsychotic; Schizophrenia; Multi-target compound; GPCR; Arylpiperazine; 5-HT1A RECEPTORS; SCHIZOPHRENIA; ANTIDEPRESSANT; CONFORMATION; CLOZAPINE; EFFICACY; ANXIETY;

D O I：

10.1016/j.ejmech.2023.115285

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Schizophrenia is a mental disorder with a complex pathomechanism involving many neurotransmitter systems. Among the currently used antipsychotics, classical drugs acting as dopamine D2 receptor antagonists, and drugs of a newer generation, the so-called atypical antipsychotics, can be distinguished. The latter are characterized by a multi-target profile of action, affecting, apart from the D2 receptor, also serotonin receptors, in particular 5HT2A and 5-HT1A. Such profile of action is considered superior in terms of both efficacy in treating symptoms and safety. In the search for new potential antipsychotics of such atypical receptor profile, an attempt was made to optimize the arylpiperazine based virtual hit, D2AAK3, which in previous studies displayed an affinity for D2, 5HT1A and 5-HT2A receptors, and showed antipsychotic activity in vivo. In this work, we present the design of D2AAK3 derivatives (1-17), their synthesis, and structural and pharmacological evaluation. The obtained compounds show affinities for the receptors of interest and their efficacy as antagonists/agonists towards them was confirmed in functional assays. For the selected compound 11, detailed structural studies were carried out using molecular modeling and X-ray methods. Additionally, ADMET parameters and in vivo antipsychotic activity, as well as influence on memory and anxiety processes were evaluated in mice, which indicated good therapeutic potential and safety profile of the studied compound.

引用

页数：18