5005-36-7Relevant articles and documents
Synthesis of novel pyrido[1,2-c]pyrimidine derivatives with 6-fluoro-3-(4-piperidynyl)-1,2-benzisoxazole moiety as potential ssri and 5-ht1a receptor ligands
Król, Marek,?lifirski, Grzegorz,Kleps, Jerzy,Ulenberg, Szymon,Belka, Mariusz,Baczek, Tomasz,Siwek, Agata,Stachowicz, Katarzyna,Szewczyk, Bernadeta,Nowak, Gabriel,Duszyńska, Beata,Herold, Franciszek
, p. 1 - 21 (2021/03/01)
Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a–i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by1H and13C NMR spectroscopy and ESI-HRMS spectrome-try. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a–i and 7a–i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d.
Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl)acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide
?tengl, Milan,Chodkowski, Andrzej,Dawidowski, Maciej,El Harchi, Aziza,Hancox, Jules C.,Jarkovska, Dagmar,Konopelski, Piotr,Król, Marek,Mistrova, Eliska,Podsadni, Piotr,Popowicz, Grzegorz M.,Sviglerova, Jitka,Szuberski, Piotr,Szulczyk, Bart?omiej,Tur?o, Jadwiga,Ufnal, Marcin,Wróbel, Martyna Zofia,Zhang, Yihong
, (2020/03/17)
A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the ‘classical’ maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
Synthesis of new 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands
?lifirski, Grzegorz,Król, Marek,Kleps, Jerzy,Podsadni, Piotr,Belka, Mariusz,B?czek, Tomasz,Siwek, Agata,Stachowicz, Katarzyna,Szewczyk, Bernadeta,Nowak, Gabriel,Bojarski, Andrzej,Kozio?, Anna E.,Tur?o, Jadwiga,Herold, Franciszek
, p. 383 - 397 (2019/07/19)
Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives. In vitro tests (RBA) were carried out for 10.1-10.27 compounds in order to determine their affinity to 5-HT1A receptor and SERT protein. 10.1-10.3, 10.6, 10.7, 10.16 and 10.27 compounds had high binding ability to both molecular targets (5-HT1A Ki = 8–87 nM; SERT Ki = 8–52 nM). For these compounds (10.1-10.3, 10.6, 10.7, 10.16, 10.27) further in vitro, in vivo and metabolic stability tests were performed. In vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) showed their selectivity towards 5-HT1A receptor and SERT protein. In vivo tests revealed that compounds 10.7 and 10.16 had the properties of presynaptic antagonists of the 5-HT1A receptor. The redesign of the 2H-pyrido[1,2-c]pyrimidine residue present in the terminal part towards 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine resulted in the improved metabolic stability and enhanced affinity to both molecular targets (5-HT1A-R and SERT) compared to the precursors.