N4-Unsubstituted N1-Arylpiperazines as High-Affinity 5-HT1A Receptor Ligands

Article abstract of DOI:10.1021/jm00011a014

In order to explore the structural requirements for high 5-HT_1A affinity, a series of aryl-substituted N¹-phenylpiperazines were synthesized and evaluated for their ability to displace <3H>-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-HT_1A 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, except fluoro, in this class of heterobicyclic phenylpiperazines decreased affinity in the order: ortho>para>meta.The loss of affinity in the ortho and para positions is probably due to steric factors: the substituents either cause steric hindrance with the receptor or prevent the compound from adopting the appropriate conformation for binding to the 5-HT_1A receptor.Conformational analysis combined with structure-affinity relationships (SAR) indicates that our arylpiperazines may bind at the 5-HT_1A receptor in a nearly coplanar conformation.Observed interactions of the compounds in our 5-HT_1A receptor model appeared to be in agreement with SAR data.The aromatic part of the arylpiperazine moiety has ?-? interactions with the aromatic residues Trp161 and Phe362 in helices IV and VI, respectively.The positively charged protonated basic nitrogen forms a hydrogen bond with the negative charged Asp116 in helix III.The ammonium-aspartate complex is surrounded by aromatic residues Trp358 and Phe361 in helix VI.A lipophilic pocket is formed by Phe362, Leu366 (both helix VI), and the methyl group of Thr200 (helix V).In agreement with the model, addition of a methyl substituent to the structure of the benzodioxine analogue 12 in this region, yielding 13, is favorable for 5-HT_1A receptor affinity.Unfavorable positions for substitution with bulky groups, like the 3- and 4-positions in the benzofuran compound 14, are explained by steric hindrance with the backbone atoms of helix V.Thus, we were able to rationalize the 5-HT_1A SAR of existing N¹-phenylpiperazines, as well as a series of newly synthesized bicyclic heteroarylpiperazines, in terms of receptor-ligand interactions.Several of these N⁴-unsubstituted compounds had affinities in the low-nanomolar range.