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

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.