YLPIPERAZINYL)ALKYL]THIO]THIENO[2,3-D]PYRIMIDINONE DERIVATIVES AS HIGH-AFFINITY, SELECTIVE 5-HT1A RECEPTOR LIGANDS

A series of azinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4(1H)-one and 3-s ubstituted azinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4(3H)-one derivati ves was prepared and evaluated for in vitro 5-HT1A receptor affinity b y radioligand binding assays; the selectivity for 5-HT1A receptors rat her than alpha(1)-adrenoceptors was also examined (ratio of the IC50 a lpha(1) to IC50 5-HT1A). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the su bstituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT1A ligands. The most effective derivative for displacin g [3H]-8-OH-DPAT from rat hippocampal membranes was the thio]-5,6-dime thylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0.3 nM) with selecti vity 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 22 6 nM; selectivity 5), N3 unsubstituted analogues of derivatives 70 and 73, show the importance of an amino group in position 3 of the thieno pyrimidine system for the interaction with 5-HT1A receptor binding sit es, although this fragment can affect the affinity and selectivity onl y if linked to the (arylpiperazinyl)alkyl moiety. The better selectivi ty of piperidine 74 (IC50 0.8;selectivity 45) compared to the analogou s piperazine 70 is also noteworthy. Twenty of the 30 molecules used fo r determining the binding affinity to 5-HT1A and alpha(1)-adrenergic r eceptors were selected for QSAR analysis using a series of molecular d escriptors and calculated with the TSAR software.