[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone Derivatives as High-Affinity, Selective 5-HT_1A Receptor Ligands

Abstract

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)alky]thio]thieno[2,3-d]pyrimidin-4 (3H)-one derivatives was prepared and evaluated for in vitro 5-HT1A receptor affinity by radioligand binding assays; the selectivity for 5-HT1A receptors rather than alpha 1-adrenoceptors was also examined (ratio of the IC50 alpha 1 to IC50 5-HT1A). 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-HT1A 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-HT1A over the alpha 1-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-HT1A was 6.8 nM. These results, compared to those for compounds 46 (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-HT1A 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-HT1A and alpha 1-adrenergic receptors were selected for QSAR analysis using a series of molecular descriptors and calculated with the TSAR software.

Synthesis, 5-Hydroxytryptamine_1A Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

“…This observation differs from the results reported by Heinrich et al, 14,19) where the para-methoxylated derivative in their indolebutylphenylpiperazine series are always better ligands than the unsubstituted analogues. On the other hand, our result agrees with those reported by Modica et al,24) where the presence of a para-methoxy group notably reduced the 5-HT 1A affinity in a series of arylpiperazinylthienopyrimidinones. Interestingly, in this last report the alkyl chain connecting the arylpiperazine and the thienopyrimidinone moieties was composed of 3 methylene units.…”

“…The unsubstituted indolepropylphenylpiperazine (12a) showed a marked affinity for 5-HT 1A , which increased after the introduction of a methoxyl group in the ortho position (12b). This result agrees with a number of previous studies 11,14,[24][25][26] in which the 2-methoxyarylpiperazine derivative exhibited one of the highest affinities of the series.…”

“…Finally, the 2-(1-piperazinyl)pyrimidine derivative (12h) showed high affinity for the human 5-HT 1A receptor, similar to that of the ortho-methoxylated compound (12b). Interestingly, previous studies 24) showed that this type of structural modification can lead to an increase of selectivity for 5-HT 1A receptor, but at the expense of potency. The fact that (12b) and (12h) showed virtually identical affinities suggests that the latter compound might serve as a lead for novel 5-HT 1A ligands with high potency and improved selectivity.…”

Syntheses of some new azolopyrido‐[4′,3′:4,5]thieno[2,3‐d]pyrimidines

“…• C. IR: ν = 3400, 3300, 3200, 3000, 2850, 1700, 1680, and 1600 cm [4 ,3 :4,5]thieno [3,2-e] [1,2,3,4…”

“…Furthermore, various substituted thioureas also have been reported to possess broad-spectrum anthelmintic activity [2]. Although there are many methods reported in the literature for the preparation of isothiocyanates [3], heterocyclic isothiocyanates with an ester group at the ortho position have been only recently reported [4][5][6][7][8][9][10][11]. This prompted us to investigate the utility of heterocyclic isothiocyanates with an ester group at the ortho position.…”