Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects

Zajdel, Paweł; Kos, Tomasz; Marciniec, Krzysztof; Satała, Grzegorz; Canale, Vittorio; Kamiński, Krzysztof; Hołuj, Małgorzata; Lenda, Tomasz; Koralewski, Robert; Bednarski, Marek; Nowiński, Leszek; Wójcikowski, Jacek; Daniel, W.A.; Nikiforuk, Agnieszka; Nalepa, Irena; Chmielarz, Piotr; Kuśmierczyk, Justyna; Bojarski, Andrzej J.; Popik, Piotr

doi:10.1016/j.ejmech.2018.01.002

Cited by 44 publications

(40 citation statements)

References 42 publications

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“…The animals were handling every five days before experiments to minimize the stress reaction. The protocol was adapted from the original work [37,45]. The test session comprising of two trials separated by an inter-trial interval (ITI) of 1 h was carried out on the next day.…”

Section: Methodsmentioning

confidence: 99%

The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

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Jastrzębska-Więsek

et al. 2019

IJMS

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Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1–4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties.

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Section: Methodsmentioning

confidence: 99%

The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

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Lubelska

Jastrzębska-Więsek

et al. 2019

IJMS

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“…The therapeutic effect of this drug is associated to the antagonism of D2, D3, 5HT 2a , and 5-HT 2c receptors, although it exhibits an antagonist effect on other receptors such as 5-HT 1C , 5-HT 6 , 5-HT 7 , α-1A, α-2A, H1, M1, M3, and 5-HT 1A (see Table 1) (31)(32)(33)(34)(35).…”

Section: Olanzapinementioning

confidence: 99%

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

et al. 2020

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Atypical antipsychotics (AAP) or second-generation antipsychotics are the clinical option for schizophrenia treatment during acute psychoses, but they are also indicated for maintenance during lifetime, even though they are being used for other psychiatric conditions in clinical practice such as affective disorders and autism spectrum disorder, among others. These drugs are differentiated from typical antipsychotics based on their clinical profile and are a better choice because they cause fewer side effects regarding extrapyramidal symptoms (EPS). Even though they provide clear therapeutic benefits, AAP induce peripheral effects that trigger phenotypic, functional, and systemic changes outside the Central Nervous System (CNS). Metabolic disease is frequently associated with AAP and significantly impacts the patient's quality of life. However, other peripheral changes of clinical relevance are present during AAP treatment, such as alterations in the immune and endocrine systems as well as the intestinal microbiome. These less studied alterations also have a significant impact in the patient's health status. This manuscript aims to revise the peripheral immunological, endocrine, and intestinal microbiome changes induced by AAP consumption recommended in the clinical guidelines for schizophrenia and other psychiatric disorders.

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“…The animals were handled every five days before experiments to minimize the stress reaction. This protocol was adapted from the original work [41,42]. The test session comprising two trials separated by an inter-trial interval (ITI) of 1 h was carried out on the next day.…”

Section: Novel Object Recognition (Nor) Testmentioning

confidence: 99%

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

et al. 2019

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Though the 5-HT6 serotonin receptor is an important target giving both agonists and antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no 5-HT6R ligand has reached the pharmaceutical market yet due to the too narrow chemical space of the known 5-HT6R agents and insufficient “drugability.” Recently, a new group of non-indole and non-sulfone hydantoin-triazine 5-HT6R ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the most active member. This study is focused on wider pharmacological and “druglikeness” characteristics for KMP-10. A computer-aided insight into molecular interactions with 5-HT6R has been performed. “Druglikeness” was examined using an eight-test panel in vitro, i.e., a parallel artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp) affinity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on the influence of KMP-10 on rats’ metabolism, including biochemical tests, were conducted in vivo. Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity properties in vivo, and it was found to satisfy the “druglikeness” profile in vitro for KMP-10. The compound seems to be a good lead-structure and candidate for wider pharmacological studies in search for new CNS-drugs acting via 5-HT6R.

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Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects

Cited by 44 publications

References 42 publications

The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

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