Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: part 2.
Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT(1A) receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT(1A) receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT(1A) receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with -OCH(3) or -F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT(1A) receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity.
Herold
Franciszek
F
Department of Drug Technology, Faculty of Pharmacy, Medical University of Warsaw, ul Banacha 1, 02-097 Warszawa, Poland. franciszek.herold@wum.edu.pl
Izbicki
Łukasz
Ł
Chodkowski
Andrzej
A
Dawidowski
Maciej
M
Król
Marek
M
Kleps
Jerzy
J
Turło
Jadwiga
J
Wolska
Irena
I
Nowak
Gabriel
G
Stachowicz
Katarzyna
K
Dybała
Małgorzata
M
Siwek
Agata
A
Nowak
Mateusz
M
Pieniazek
Elzbieta
E
Jarończyk
Małgorzata
M
Sylte
Ingebrigt
I
Mazurek
Aleksander P
AP
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D007035:Hypothermia / Q000188:drug therapy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D011743:Pyrimidines; D044282:Receptor, Serotonin, 5-HT1A; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors