title: Synthesis and structure-activity relationships of a new model of arylpiperazines. 8. Computational simulation of ligand-receptor interaction of 5-HT(1A)R agonists with selectivity over alpha1-adrenoceptors.
abstract: We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT(1A)R ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT(1A), K(i) = 4.1 nM; alpha(1), K(i) > 1000 nM) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Morcillo
authors.forename: Esther
authors.initials: E
authors.lastname: Fernández
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: Ignacio
authors.initials: I
authors.lastname: Tejada
authors.forename: David
authors.initials: D
authors.lastname: Ayala
authors.forename: Alma
authors.initials: A
authors.lastname: Viso
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: Mercedes
authors.initials: M
authors.lastname: Delgado
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
authors.forename: José A
authors.initials: JA
authors.lastname: Fuentes
mesh_terms: D000262:Adenylyl Cyclases / Q000096:biosynthesis; D058646:Adrenergic alpha-1 Receptor Agonists; D000595:Amino Acid Sequence; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D004924:Escape Reaction / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016415:Sequence Alignment; D058825:Serotonin 5-HT1 Receptor Agonists; D013237:Stereoisomerism
chemical_list: C479225:2-((4-(naphth-1-yl)piperazin-1-yl)methyl)-1,4-dioxoperhydropyrrolo(1,2-a)pyrazine; D058646:Adrenergic alpha-1 Receptor Agonists; D010879:Piperazines; D011719:Pyrazines; D058825:Serotonin 5-HT1 Receptor Agonists; D000262:Adenylyl Cyclases