5-HT1A-VERSUS D-2-RECEPTOR SELECTIVITY OF FLESINOXAN AND ANALOGOUS N-4-SUBSTITUTED N-1-ARYLPIPERAZINES

We investigated the structural requirements for high 5-HT1A affinity o f the agonist flesinoxan and its selectivity versus D-2 receptors. For this purpose a series of arylpiperazine congeners of flesinoxan were synthesized and evaluated for their ability to displace [H-3]-8-OH-DPA T and [H-3]spiperone from their specific binding sites in rat frontal cortex homogenates and rat striatum, respectively. Variations were mad e in the N-4-substituent and the arylpiperazine region. Effects of N-4 -substitution in the investigated compounds appeared to be quite simil ar for 5-HT1A- and D-2-receptor affinity. Lipophilicity at a distance of four carbon atoms from the piperazine N-4 atom seems to be the main contributing factor to affinity for both receptors. Our data show tha t the amide group in the flesinoxan N-4-substituent is unlikely to int eract with the 5-HT1A receptor but, instead, acts as a spacer. In cont rast to the structure-affinity relationships (SARs) of the N-4-substit uents, selectivity for 5-HT1A versus D-2 receptors was gained by the a rylpiperazine substitution pattern of flesinoxan. Restriction of flexi bility of the N-4-(benzoylamino)ethyl substituent and its effect on 5- HT1A-receptor affinity and activity were also studied. Our data show t hat in the bioactive conformation, the N-4-[(p-fluorobenzoyl)amino]eth yl substituent is probably directed anti-periplanar relative to the H- N4 atom. These results were used to dock flesinoxan (1) and two of its congeners (27 and 33) into a model of the 5-HT1A receptor that we pre viously reported. Amino acid residues surrounding the N-4-[(p-fluorobe nzoyl)amino]ethyl substituent of flesinoxan and its congeners are also present in D-2 receptors. In contrast, several residues that contact the benzodioxane moiety differ from those in D-2 receptors. These obse rvations from the 3D model agree with the 5-HT1A SAR data and probably account for the selectivity of flesinoxan versus D-2 receptors.