Synthesis and receptor binding of new thieno[2,3-d]-pyrimidines as selective ligands of 5-HT(3) receptors.
With the aim to develop new potent and selective ligands of 5-HT(3)-type serotonin receptors and to acquire more information on their structure-affinity relationships, new thieno[2,3-d]pyrimidine derivatives 32-39 were synthesized and their binding to 5-HT(3) versus 5-HT(4 )receptors was studied. Some of these new compounds exhibit good affinity for cortical 5-HT(3) receptors, but not for 5-HT(4) receptors. Among these derivatives, 6-ethyl-4-(4-methyl-1-piperazinyl)-2-(methylthio)thieno[2,3-d]pyrimidine 32 is the most potent ligand (K(i) = 67 nM); it behaves as a competitive antagonist of the 5-HT(3) receptor function in the guinea pig colon. Its binding interactions with 5-HT(3A )receptors were analysed by using receptor modelling and comparative docking.
Dipartimento di Scienze Farmaceutiche, Università di Catania, Catania, Italy. mmodica@unict.it
Maria N
MN
Modica
Giuseppe
G
Romeo
Loredana
L
Salerno
Valeria
V
Pittalà
Maria A
MA
Siracusa
Ilario
I
Mereghetti
Alfredo
A
Cagnotto
Tiziana
T
Mennini
Róbert
R
Gáspár
Adrienn
A
Gál
George
G
Falkay
Márta
M
Palkó
Gábor
G
Maksay
Ferenc
F
Fülöp
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C531050:6-ethyl-4-(4-methyl-1-piperazinyl)-2-(methylthio)thieno(2,3-d)pyrimidine; D008024:Ligands; D011743:Pyrimidines; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D013876:Thiophenes; D044422:Receptors, Serotonin, 5-HT4