W. Kuipers et al., N-4-UNSUBSTITUTED N-1-ARYLPIPERAZINES AS HIGH-AFFINITY 5-HT1A RECEPTOR LIGANDS, Journal of medicinal chemistry, 38(11), 1995, pp. 1942-1954
In order to explore the structural requirements for high 6-HT1A affini
ty, a series of aryl-substituted N-1-phenylpiperazines were synthesize
d and evaluated for their ability to displace [H-3]-8-OH-DPAT from its
specific binding sites in rat frontal cortex homogenates. We found 2-
methoxy substitution to be favorable, while 4-methoxy substitution was
detrimental for 5-HT1A affinity. Substitution with annelated rings at
the 2,3-positions was highly favorable for all investigated compounds
, with the exception of a pyrrole ring. All other substitutions, excep
t fluoro, in this class of heterobicyclic phenylpiperazines decreased
affinity in the order: ortho > para > meta. The loss of affinity in th
e ortho and para positions is probably due to steric factors: the subs
tituents either cause steric hindrance with the receptor or prevent th
e compound from adopting the appropriate conformation for binding to t
he 5-HT1A receptor. Conformational analysis combined with structure-af
finity relationships (SAR) indicates that our arylpiperazines may bind
at the 5-HT1A receptor in a nearly coplanar conformation. Observed in
teractions of the compounds in our 5-HT1A receptor model appeared to b
e in agreement with SAR data. The aromatic part of the arylpiperazine
moiety has pi-pi interactions with the aromatic residues Trp161 and Ph
e362 in helices IV and VI, respectively. The positively charged proton
ated basic nitrogen forms a hydrogen bond with the negatively charged
Asp116 in helix III. The ammonium-aspartate complex is surrounded by a
romatic residues Trp358 and Phe361 in helix VI. A lipophilic pocket is
formed by Phe362, Leu366 (both helix VI), and the methyl group of Thr
200 (helix V). In agreement with the model, addition of a methyl subst
ituent to the structure of the benzodioxine analogue 12 in this region
, yielding 13, is favorable for 5-HT1A receptor affinity. Unfavorable
positions for substitution with bulky groups, like the 3- and 4-positi
ons in the benzofuran compound 14, are explained by steric hindrance w
ith the backbone atoms of helix V. Thus, we were able to rationalize t
he 5-HT1A SAR of existing N-1-phenylpiperazines, as well as a series o
f newly synthesized bicyclic heteroarylpiperazines, in terms of recept
or-ligand interactions. Several of these N-4-unsubstituted compounds h
ad affinities in the low-nanomolar range.