1-aryl-4-[(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)alkyl]piperazines and their analogues: Influence of the stereochemistry of the tetrahydronaphthalen-1-yl nucleus on 5-HT1A receptor affinity and selectivity versus alpha(1) and D-2 receptors. 5

Some 1-aryl-4-[(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piper azines and their alkylamino and alkylamido analogues, previously studied as 5-HT1A ligands, were prepared in enantiomerically pure form, and their abs olute configuration was det;ermined by chemical correlation or by chiroptic al properties. They were evaluated for in vitro 5-HT1A, D-2, and alpha(1) r eceptor affinity by radioligand binding assays, to study the influence of t he chiral carbon atom of the tetrahydronaphthalene nucleus on the 5-HT1A af finity and selectivity. Results indicated that, as regarding the 5-HT1A rec eptor affinity, there was no difference in affinity between (-)- and (+)-en antiomers as well as the racemate of each compound. The stereochemistry, in stead, influenced the selectivity: all (-)-enantiomers displayed affinity v alues higher than those of (+)-isomers at D-2 receptors, and conversely, al l (+)-enantiomers displayed affinity values higher than those of (-)-isomer s at alpha(1) receptors. As a result of this trend, it is not possible to p redict the isomer with a better selectivity profile. However, compounds (S) -(+)-2, (S)-(+)-4, and (R)-(+)-6 displayed high affinity for the 5-HT1A rec eptor (IC50 values ranging between 7.0 and 2.3 nM) and good selectivity (gr eater than or equal to 250-fold) versus both D-2 and alpha(1) receptors. Fu rthermore, compounds (S)-(+)-4 and (R)-(-)-4 were submitted to the [S-35]GT P gamma S binding assay for a preliminary evaluation of their intrinsic act ivity on the 5-HT1A receptor.