| Abstract
| - Some 1-aryl-4-[(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazines and theiralkylamino and alkylamido analogues, previously studied as 5-HT1A ligands, were prepared inenantiomerically pure form, and their absolute configuration was determined by chemicalcorrelation or by chiroptical properties. They were evaluated for in vitro 5-HT1A, D2, and α1receptor affinity by radioligand binding assays, to study the influence of the chiral carbon atomof the tetrahydronaphthalene nucleus on the 5-HT1A affinity and selectivity. Results indicatedthat, as regarding the 5-HT1A receptor affinity, there was no difference in affinity between(−)- and (+)-enantiomers as well as the racemate of each compound. The stereochemistry,instead, influenced the selectivity: all (−)-enantiomers displayed affinity values higher thanthose of (+)-isomers at D2 receptors, and conversely, all (+)-enantiomers displayed affinityvalues higher than those of (−)-isomers at α1 receptors. As a result of this trend, it is notpossible to predict the isomer with a better selectivity profile. However, compounds (S)-(+)-2,(S)-(+)-4, and (R)-(+)-6 displayed high affinity for the 5-HT1A receptor (IC50 values rangingbetween 7.0 and 2.3 nM) and good selectivity (≥250-fold) versus both D2 and α1 receptors.Furthermore, compounds (S)-(+)-4 and (R)-(−)-4 were submitted to the [35S]GTPγS bindingassay for a preliminary evaluation of their intrinsic activity on the 5-HT1A receptor.
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