5-HT1A- versus D2-Receptor Selectivity of Flesinoxan and Analogous N 4-Substituted N 1-Arylpiperazines
journal contribution
posted on 1997-01-31, 00:00 authored by Wilma Kuipers, Chris G. Kruse, Ineke van Wijngaarden, Piet J. Standaar, Martin Th. M. Tulp, Nora Veldman, Anthony L. Spek, Adriaan P. IJzermanWe investigated the structural requirements for high
5-HT1A affinity of the agonist flesinoxan
and its selectivity versus D2 receptors. For this
purpose a series of arylpiperazine congeners
of flesinoxan were synthesized and evaluated for their ability to
displace [3H]-8-OH-DPAT and
[3H]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 D2-receptor affinity.
Lipophilicity at a distance of four carbon atoms from
the
piperazine N4 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 D2 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 HN4
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 D2 receptors. In contrast, several residues that
contact the benzodioxane moiety differ from
those in D2 receptors. These observations from the 3D
model agree with the 5-HT1A SAR data
and probably account for the selectivity of flesinoxan versus
D2 receptors.
