Title:Discovery and Development of Non-Dopaminergic Agents for the Treatment of Schizophrenia: Overview of the Preclinical and Early Clinical Studies
Volume: 26
Issue: 25
Author(s): Agnieszka Jankowska, Grzegorz Satała, Anna Partyka, Anna Wesołowska*, Andrzej J. Bojarski, Maciej Pawłowski and Grażyna Chłoń-Rzepa*
Affiliation:
- Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow,Poland
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow,Poland
Keywords:
Schizophrenia, mGlu receptor ligands, GABAA receptor ligands, α7 nACh receptor agonists, GlyT1
inhibitors, GSK-3 inhibitors, PDE inhibitors, 5-HT receptor ligands.
Abstract: Schizophrenia is a chronic psychiatric disorder that affects about 1 in 100 people around
the world and results in persistent emotional and cognitive impairments. Untreated schizophrenia
leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine
D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine
hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates
other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate
homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations
also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as
well as the role of the immune system. The purpose of this review is to update the most recent reports
on the discovery and development of non-dopaminergic agents that may reduce positive, negative,
and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics.
This review collects the chemical structures of representative compounds targeting metabotropic
glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine
receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in
vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing
the safety and efficacy of the tested compounds have also been presented. Finally, attention has been
paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity
as novel strategies in the search for dedicated medicines for patients with schizophrenia.
