title: Synthesis and in vitro pharmacological evaluation of novel 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands.
abstract: This paper reports the synthesis of new norbornene and exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide derivatives and their binding to the 5-HT1A , 5-HT2A , and 5-HT2C receptors, in order to identify selective ligands for these 5-hydroxytryptamine (5-HT, serotonine) receptor subtypes. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4-substituted piperazine) known to be critical for affinity to 5-HT1A receptors and the proper selection of substituents led to compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected and further evaluated for their binding affinities to D1 , D2 dopaminergic and α1 , α2 adrenergic receptors. 4-[3-[4-(2-Furoyl)piperazin-1-yl]propoxy-2-ol]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione 3e with Ki  = 5.04 ± 0.227 nM was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin receptors, and the most selective derivative versus dopaminergic and adrenergic receptors.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II", Napoli, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Fiorino
authors.forename: Elisa
authors.initials: E
authors.lastname: Magli
authors.forename: Beatrice
authors.initials: B
authors.lastname: Severino
authors.forename: Angela
authors.initials: A
authors.lastname: Corvino
authors.forename: Antonio
authors.initials: A
authors.lastname: Ciano
authors.forename: Elisa
authors.initials: E
authors.lastname: Perissutti
authors.forename: Francesco
authors.initials: F
authors.lastname: Frecentese
authors.forename: Paola
authors.initials: P
authors.lastname: Massarelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Nencini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Santagada
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Caliendo
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015195:Drug Design; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin
keywords: 5-HT1A receptor ligands; Arylpiperazine derivatives; Norbornene nucleus; Serotonin; exo-N-Hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide