N-4-UNSUBSTITUTED N-1-ARYLPIPERAZINES AS HIGH-AFFINITY 5-HT1A RECEPTOR LIGANDS

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.