title: New 5-hydroxytryptamine(1A) receptor ligands containing a norbornene nucleus: synthesis and in vitro pharmacological evaluation.
abstract: New arylpiperazine derivatives were prepared to identify highly selective and potent ligands for the 5-hydroxytryptamine 1A (5-HT(1A)) receptor as potential pharmacological tools in studies of central nervous system (CNS) disorders. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain, and arylpiperazine) known to introduce 5-HT(1A) receptor affinity and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in the nanomolar and subnanomolar ranges at 5-HT(1A) and moderate to no affinity for other relevant receptors (5-HT(2A), 5-HT(2C), D(1), D(2), alpha(1), and alpha(2)). The 4-[3-[4-(o-methoxyphenyl)piperazin-1-yl]propoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione, with K(i) = 0.021 nM, was the most active and selective derivative for the 5-HT(1A) receptor with respect to other serotonin receptors, whereas the most selective derivative for dopaminergic and adrenergic receptors was a CF(3)-substituted arylpiperazine. As a general trend, compounds with a piperazinylpropoxy chain showed a preferential affinity for the 5-HT(1A) receptor, suggesting that the alkyl chain length represents a critical structural feature in determining 5-HT(1A) receptor affinity and selectivity, as confirmed by the molecular modeling invoked for explaining the differential binding affinities of the new arylpiperazines.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Fiorino
authors.forename: Elisa
authors.initials: E
authors.lastname: Perissutti
authors.forename: Beatrice
authors.initials: B
authors.lastname: Severino
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Santagada
authors.forename: Donatella
authors.initials: D
authors.lastname: Cirillo
authors.forename: Sara
authors.initials: S
authors.lastname: Terracciano
authors.forename: Paola
authors.initials: P
authors.lastname: Massarelli
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Bruni
authors.forename: Elga
authors.initials: E
authors.lastname: Collavoli
authors.forename: Christian
authors.initials: C
authors.lastname: Renner
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Caliendo
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D009636:Norbornanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C504519:4-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4-azatricyclo(5.2.1.02,6)dec-8-ene-3,5-dione; D006575:Heterocyclic Compounds, 3-Ring; D009636:Norbornanes; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D044282:Receptor, Serotonin, 5-HT1A