title: A new class of arylpiperazine derivatives: the library synthesis on SynPhase lanterns and biological evaluation on serotonin 5-HT(1A) and 5-HT(2A) receptors.
abstract: An efficient solid-supported method for the synthesis of a new class of arylpiperazine derivatives containing amino acid residues has been developed. A 72-membered library was synthesized on SynPhase Lanterns functionalized by a BAL linker. A one-pot cleavage/cyclization step of aspartic and glutamic acid derivatives yielded succinimide- and pyroglutamyl-containing ligands (chemsets 9 and 10). The library representatives under study showed different levels of affinity for 5-HT(1A) and 5-HT(2A) receptors (estimated K(i) = 24-4000 and 1-2130 nM, respectively). Several dual 5-HT(1A)/5-HT(2A) ligands were found, of which two (9(3,3) and 9(3,5)) displayed high 5-HT(2A) affinity comparable to that of the reference drug ritanserin. A set of individual fragment contributions for the prediction of 5-HT(1A) and 5-HT(2A) affinity of all the library members were defined on the basis of the Free-Wilson analysis of 26 compounds. An alkylarylpiperazine fragment had essentially the same impact on the affinity for both receptors, whereas different terminal amide fragments were preferred by 5-HT(1A) (chemset 17, R(2) = adamantyl) and 5-HT(2A) (chemset 9, R(2) = norborn-2-ylmethyl) binding sites.
authors.affiliation: Laboratoire des Aminoacides, Peptides, et Protéines, UMR 5810, Faculté de Pharmacie, Université Montpellier I et II, 15 avenue Charles Flahault, 34060 Montpellier, France. mfzajdel@cyf-kr.edu.pl
authors.forename: Paweł
authors.initials: P
authors.lastname: Zajdel
authors.forename: Gilles
authors.initials: G
authors.lastname: Subra
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Beata
authors.initials: B
authors.lastname: Duszyńska
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
mesh_terms: D020650:Combinatorial Chemistry Techniques; D003432:Cross-Linking Reagents; D006801:Humans; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D003432:Cross-Linking Reagents; D008024:Ligands; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D044282:Receptor, Serotonin, 5-HT1A