Antidepressant and antipsychotic activity of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT₁A/5-HT₂A/5-HT₇ and dopamine D₂/D₃ receptors

Paweł Zajdel; Krzysztof Marciniec; Andrzej Maślankiewicz; Katarzyna Grychowska; Grzegorz Satała; Beata Duszyńska; Tomasz Lenda; Agata Siwek; Gabriel Nowak; Anna Partyka; Dagmara Wróbel; Magdalena Jastrzębska-Więsek; Andrzej J Bojarski; Anna Wesołowska; Maciej Pawłowski

doi:10.1016/j.ejmech.2012.11.042

Antidepressant and antipsychotic activity of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT₁A/5-HT₂A/5-HT₇ and dopamine D₂/D₃ receptors

Eur J Med Chem. 2013 Feb:60:42-50. doi: 10.1016/j.ejmech.2012.11.042. Epub 2012 Dec 5.

Authors

Paweł Zajdel¹, Krzysztof Marciniec, Andrzej Maślankiewicz, Katarzyna Grychowska, Grzegorz Satała, Beata Duszyńska, Tomasz Lenda, Agata Siwek, Gabriel Nowak, Anna Partyka, Dagmara Wróbel, Magdalena Jastrzębska-Więsek, Andrzej J Bojarski, Anna Wesołowska, Maciej Pawłowski

Affiliation

¹ Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. pawel.zajdel@uj.edu.pl

PMID: 23279866
DOI: 10.1016/j.ejmech.2012.11.042

Abstract

A series of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole was synthesized to explore the influence of two structural features - replacement of ether/amide moiety with sulfonamide one, and localization of a sulfonamide group in the azine moiety. In contrast to aripiprazole, compound 33 (N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)quinoline-7-sulfonamide) and 39 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-3-sulfonamide) displaying multireceptor 5-HT(1A)/5-HT(2A)/5-HT(7)/D(2)/D(3) profile, and behaving as 5-HT(1A) agonists, D(2) partial agonists, and 5-HT(2A)/5-HT(7) antagonists, produced significant antidepressant activity in FST in mice. On the other hand, their 4-isoquinolinyl analog 40 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-4-sulfonamide), with similar receptor binding and functional profile, additionally displayed remarkable antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents / chemical synthesis
Antidepressive Agents / chemistry
Antidepressive Agents / pharmacology*
Antipsychotic Agents / chemical synthesis
Antipsychotic Agents / chemistry
Antipsychotic Agents / pharmacology*
Aripiprazole
Behavior, Animal / drug effects
Dizocilpine Maleate / pharmacology
Dopamine D2 Receptor Antagonists*
Dose-Response Relationship, Drug
Isoquinolines / chemical synthesis
Isoquinolines / chemistry
Isoquinolines / pharmacology
Mice
Molecular Structure
Motor Activity / drug effects
Piperazines / chemical synthesis
Piperazines / chemistry*
Piperazines / pharmacology*
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology
Quinolones / chemical synthesis
Quinolones / chemistry*
Quinolones / pharmacology*
Receptors, Dopamine D2 / metabolism
Receptors, Dopamine D3 / antagonists & inhibitors*
Receptors, Dopamine D3 / metabolism
Receptors, Serotonin / metabolism*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology

Substances

Antidepressive Agents
Antipsychotic Agents
Dopamine D2 Receptor Antagonists
Isoquinolines
Piperazines
Quinolines
Quinolones
Receptors, Dopamine D2
Receptors, Dopamine D3
Receptors, Serotonin
Sulfonamides
Dizocilpine Maleate
Aripiprazole