W. Kuipers et al., 5-HT1A-VERSUS D-2-RECEPTOR SELECTIVITY OF FLESINOXAN AND ANALOGOUS N-4-SUBSTITUTED N-1-ARYLPIPERAZINES, Journal of medicinal chemistry, 40(3), 1997, pp. 300-312
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.