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 of 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-DPAT and [H-3]spiperone from their specific binding sites in rat frontal cortex homogenates and rat striatum, respectively. Variations were made in the N-4-substituent and the arylpiperazine region. Effects of N-4-substitution in the investigated compounds appeared to be quite similar 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 that the amide group in the flesinoxan N-4-substituent is unlikely to interact with the 5-HT1A receptor but, instead, acts as a spacer. In contrast to the structure-affinity relationships (SARs) of the N-4-substituents, selectivity for 5-HT1A versus D-2 receptors was gained by the arylpiperazine substitution pattern of flesinoxan. Restriction of flexibility of the N-4-(benzoylamino)ethyl substituent and its effect on 5-HT1A-receptor affinity and activity were also studied. Our data show that in the bioactive conformation, the N-4-[(p-fluorobenzoyl)amino]ethyl 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 previously reported. Amino acid residues surrounding the N-4-[(p-fluorobenzoyl)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 observations from the 3D model agree with the 5-HT1A SAR data and probably account for the selectivity of flesinoxan versus D-2 receptors.