[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives as high-affinity, selective 5-HT(1A) receptor ligands

Maria Modica, Maria Santagati, Filippo Russo, Luca Parotti, Luca De Gioia, Carlo Selvaggini, Mario Salmona, Tiziana Mennini

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A series of 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3- d]pyrimidin-4(1H)-one and 3-substituted 2-[[(4-aryl-1- piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4(3H)-one derivatives was prepared and evaluated for in vitro 5-HT(1A) receptor affinity by radioligand binding assays; the selectivity for 5-HT(1A) receptors rather than α1- adrenoceptors was also examined (ratio of the IC50 α1 to IC50 5- HT(1A)). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the substituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT(1A) ligands. The most effective derivative for displacing [3H]-8-OH-DPAT from rat hippocampal membranes was the 3-amino-2-[[3-[4-(2-methoxyphenyl)-1- piperazinyl]propyl]thio]-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0.3 nM) with selectivity of 24 for the 5-HT(1A) over the α1- adrenoceptor. Compound 73, where the 2-methoxyphenyl on the N4 piperazine ring was replaced with a pyrimidine group, showed the best selectivity, with a ratio of 74, while its affinity IC50 for 5-HT(1A) was 6.8 nM. These results, compared to those for compounds 40 (IC50 24 nM; selectivity 2) and 49 (IC50 226 nM; selectivity 5), N3 unsubstituted analogues of derivatives 70 and 73, show the importance of an amino group in position 3 of the thienopyrimidine system for the interaction with 5-HT(1A) receptor binding sites, although this fragment can affect the affinity and selectivity only if linked to the (arylpiperazinyl)alkyl moiety. The better selectivity of piperidine 74 (IC50 0.8; selectivity 45) compared to the analogous piperazine 70 is also noteworthy. Twenty of the 30 molecules used for determining the binding affinity to 5-HT(1A) and α1-adrenergic receptors were selected for QSAR analysis using a series of molecular descriptors and calculated with the TSAR software.

Original languageEnglish
Pages (from-to)574-585
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number4
Publication statusPublished - Feb 14 1997

ASJC Scopus subject areas

  • Organic Chemistry


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