Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 4.
Eur J Med Chem
; 90: 21-32, 2015 Jan 27.
Article
in En
| MEDLINE
| ID: mdl-25461308
ABSTRACT
This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R3 = Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested. A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified Ki 5-HT1A = 12.4 nM; Ki SERT = 15.6 nM 8.1; Ki 5-HT1A = 5.6 nM; Ki SERT = 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT1AR. The presence of chlorine (R3) in this series resulted in a notable reduction in binding to both targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R1 and R2 substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidines
/
Selective Serotonin Reuptake Inhibitors
/
Receptor, Serotonin, 5-HT1A
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2015
Document type:
Article
Affiliation country:
Polonia