RT Journal Article
T1 Discovery of novel arylpiperazine-based DA/5-HT modulators as potential antipsychotic agents – Design, synthesis, structural studies and pharmacological profiling
A1 Stępnicki, Piotr
A1 Targowska-Duda, Katarzyna M.
A1 Martínez Rodríguez, Antón Leandro
A1 Zięba, Agata
A1 Wronikowska-Denysiuk, Olga
A1 Wróbel, Martyna Z.
A1 Bartyzel, Agata
A1 Trzpil, Alicja
A1 Wróbel, Tomasz M.
A1 Chodkowski, Andrzej
A1 Mirecka, Karolina
A1 Karcz, Tadeusz
A1 Szczepańska, Katarzyna
A1 Loza García, María Isabel
A1 Budzyńska, Barbara
A1 Turło, Jadwiga
A1 Handzlik, Jadwiga
A1 Fornal, Emilia
A1 Poleszak, Ewa
A1 Castro Pérez, María de los Ángeles
A1 Kaczor, Agnieszka A.
K1 Antipsychotic
K1 Schizophrenia
K1 Multi-target compound
K1 GPCR
K1 Arylpiperazine
AB 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 5-HT2A 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, 5-HT1A 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.
PB Elsevier Masson s.r.l.
SN 0223-5234
YR 2023
FD 2023-04-05
LK https://hdl.handle.net/10347/39462
UL https://hdl.handle.net/10347/39462
LA eng
NO Stępnicki P, Targowska-Duda KM, Martínez AL, Zięba A, Wronikowska-Denysiuk O, Wróbel MZ, Bartyzel A, Trzpil A, Wróbel TM, Chodkowski A, Mirecka K, Karcz T, Szczepańska K, Loza MI, Budzyńska B, Turło J, Handzlik J, Fornal E, Poleszak E, Castro M, Kaczor AA. Discovery of novel arylpiperazine-based DA/5-HT modulators as potential antipsychotic agents - Design, synthesis, structural studies and pharmacological profiling. Eur J Med Chem. 2023 Apr 5;252:115285.
DS Minerva
RD 24 abr 2026