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Eur J Med Chem. 2018 Feb 10;145:790-804. doi: 10.1016/j.ejmech.2018.01.002. Epub 2018 Jan 3.

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

Author information

1
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: pawel.zajdel@uj.edu.pl.
2
Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
3
Department of Organic Chemistry, Medical University of Silesia, 4 Jagiellońska Street, 41-200 Sosnowiec, Poland.
4
Department of Medicinal Chemistry, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
5
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
6
Department of Brain Biochemistry, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
7
TriMen Chemicals, 141 Piłsudskiego Avenue, 92-318 Łódź, Poland.
8
Department of Pharmacological Screening, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
9
Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
10
Department of Neuro and Psychopharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
11
Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland. Electronic address: nfpopik@cyf-kr.edu.pl.

Abstract

Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D2 receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HT1AR agonism, 5-HT2A/5-HT7/D2/D3R antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.

KEYWORDS:

5-HT(1A) partial agonist; 5-HT(7) antagonist; Cognitive flexibility; Designed multiple ligands; Dopamine D(2) receptors; Multitarget directed ligands; Polypharmacology; Schizophrenia

PMID:
29407591
DOI:
10.1016/j.ejmech.2018.01.002
[Indexed for MEDLINE]

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