Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors. Part 4.
New 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione derivatives of arylpiperazine (6-18) were prepared and evaluated in vitro for their affinity for 5-HT1A, 5-HT2A, and alpha1 receptors. The influence of ortho substitution in the phenyl ring, substitution at position 4 of the pyrido[1,2-c]pyrimidine system, and its unsaturation degree were explored. The tested compounds showed high affinity for the 5-HT1A receptor (Ki = 1.3-79.2 nM) and moderate to low affinity for the 5-HT2A (Ki = 51.7-1405 nM) and alpha1 receptors (Ki = 19.7-382.3 nM). Compounds 8 and 10 showed the highest 5-HT1A receptor affinity (Ki = 1.3 and 2.2 nM, respectively) and were 37- and 35.9-fold, respectively, more selective in relation to alpha1 adrenoreceptors.
Herold
Franciszek
F
Department of Drug Technology, Faculty of Pharmacy, The Medical University of Warsaw, ul. Banacha 1, 02-097 Warszawa, Poland. herold@farm.amwaw.edu.pl
Król
Marek
M
Kleps
Jerzy
J
Nowak
Gabriel
G
D000302:Adrenal Cortex / Q000187:drug effects; D000818:Animals; D008024:Ligands; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D010879:Piperazines; D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; C483405:octahydropyrido(1,2-c)pyrimidine; D044282:Receptor, Serotonin, 5-HT1A