High affinity and selectivity of [[(arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives for the 5-HT1A receptor. Synthesis and structure-affinity relationships

In this work we report the affinity of new thienopyrimidinones for 5-HT(1A) Rs and the selectivity versus alpha(1)ARs. The 3-amino-2-[[3-[4-(2-methoxyp henyl)-1-piperazinyl]propyl]thio]-6-ethyl-thieno[2,3-d]pyrimidin-4(3H)-one 27 is the most potent and selective (Ki 0.19 nM, selectivity 115). Compound 31 with the N4 piperazine orthonitrophenyl nucleus instead of the orthomet hoxyphenyl also shows a good affinity and selectivity (Ki 1.46 nM, selectiv ity 84). The results of derivatives 28, 29 and 30 (Ki 3.28, 12.59 and 4.38 nM; selectivity 24, 4 and 5, respectively), which have, respectively, an et hyl, an allyl and an acetylamino group instead of an N3 amino group, indica te the importance of this last group for the interaction with 5-HT1AR. Comp arison of the results for the superior homologue 53 (Ki 3.72 nM, selectivit y 51) and the inferior homologue 52 (5-HT1A Ki 1 499 nM, alpha(1)A Ki NA) o f 2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-6,7-dimethyl-8H-[1,3,4]thi adiazolo[3,2-a]thieno[2,3-d]pyrimidin-8-one 57 (Ki 23 nM, selectivity 5) sh ows how important the length of the chain binding the two heterocyclic syst ems is in the interaction with 5-HT(1A)Rs and alpha(1)ARs. (C) 2000 Edition s scientifiques et medicales Elsevier SAS.