- Novel spirohydantoin derivative as a potent multireceptor-active antipsychotic and antidepressant agent
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Abstract A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D2 receptors. Based on these data, four comp
- Czopek, Anna,Ko?aczkowski, Marcin,Bucki, Adam,Byrtus, Hanna,Paw?owski, Maciej,Kazek, Grzegorz,Bojarski, Andrzej J.,Piaskowska, Agata,Kalinowska-T?ücik, Justyna,Partyka, Anna,Weso?owska, Anna
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- Novel serotonin 5-HT2A receptor antagonists derived from 4-phenylcyclohexane-5-spiro-and 5-methyl-5-phenyl-hydantoin, for use as potential antiplatelet agents
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Background: Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT2A receptor antagonists could constitute alternative antiplatelet therapy. Methods: Based on the structures of the conventional 5-HT2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT2A receptors using isolated rat aorta and cells expressing human 5-HT2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT2A receptor antagonists. Moreover, the structure–activity relationships were studied following molecular docking to the 5-HT2A receptor model. Results: Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC50 = 27.3?μM) being more active than sarpogrelate (IC50 = 66.8?μM) and comparable with ketanserin (IC50 = 32.1?μM). Moreover, compounds 2–5, 9–11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation. Conclusions: Our study confirmed that the 5-HT2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action.
- Czopek, Anna,Kubacka, Monika,Bucki, Adam,Siwek, Agata,Filipek, Barbara,Paw?owski, Maciej,Ko?aczkowski, Marcin
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p. 1361 - 1372
(2021/06/15)
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- New spirohydantoin derivatives - Synthesis, pharmacological evaluation, and molecular modeling study
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A series of new arylpiperazinylpropyl derivatives of 8/6-phenyl-1,3-diazaspiro[4.5]decan-2,4-dione and spiro[imidazolidine-4,1′-indene/naphthalene]-2,5-dione was synthesized and their affinity was evaluated toward serotonin 5-HT1A, 5-HT2A
- Czopek, Anna,Zagórska, Agnieszka,Ko?aczkowski, Marcin,Bucki, Adam,Gryz?o, Beata,Rychtyk, Joanna,Paw?owski, Maciej,Siwek, Agata,Sata?a, Grzegorz,Bojarski, Andrzej,Kubacka, Monika,Filipek, Barbara
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p. 1545 - 1554
(2016/12/18)
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- Discovery of 1-amino-4-phenylcyclohexane-1-carboxylic acid and its influence on agonist selectivity between human melanocortin-4 and -1 receptors in linear pentapeptides
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Linear pentapeptides (Penta-cis-Apc-DPhe-Arg-Trp-Gly-NH2) containing 1-amino-4-phenylcyclohexane-1-carboxylic acid (cis-Apc) and substituted Apc are potent hMC4R agonists and they are inactive or weakly active in hMC1R, hMC3R, and hMC5R agonist assays. This study, together with our earlier report on 5-BrAtc, demonstrated the importance of replacing His 6 with phenyl-containing rigid templates in achieving good hMC4R agonist potency and selectivity against hMC1R in linear pentapeptides.
- Chu, Xin-Jie,Bartkovitz, David,Danho, Waleed,Swistok, Joseph,Cheung, Adrian Wai-Hing,Kurylko, Grazyna,Rowan, Karen,Yeon, Mitch,Franco, Lucia,Qi, Lida,Chen, Li,Yagaloff, Keith
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p. 4910 - 4914
(2007/10/03)
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