title: Synthesis and in vitro pharmacological evaluation of a new series of 5-HT1A 5-HT2A and 5-HT2C receptor ligands containing a norbornene nucleus.
abstract: A series of 4-substituted piperazine derivatives bearing a norbornene nucleus have been prepared and their affinity for serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors has been evaluated. Compounds showing the highest affinity have been selected and evaluated on dopaminergic (D1 and D2) and adrenergic (alpha1 and alpha2) receptors. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on serotonin receptors and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in nanomolar range towards 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, alpha1 and alpha2). Compound 2q 4-[2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (Ki = 1.13 nM), was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin, dopaminergic and adrenergic receptors. Moreover, compound 3p showed mixed 5-HT2A/5-HT2C activity with affinity values in nanomolar range.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fiorino
authors.forename: B
authors.initials: B
authors.lastname: Severino
authors.forename: F
authors.initials: F
authors.lastname: De Angelis
authors.forename: E
authors.initials: E
authors.lastname: Perissutti
authors.forename: E
authors.initials: E
authors.lastname: Magli
authors.forename: F
authors.initials: F
authors.lastname: Frecentese
authors.forename: A
authors.initials: A
authors.lastname: Esposito
authors.forename: P
authors.initials: P
authors.lastname: Massarelli
authors.forename: C
authors.initials: C
authors.lastname: Nencini
authors.forename: B
authors.initials: B
authors.lastname: Viti
authors.forename: V
authors.initials: V
authors.lastname: Santagada
authors.forename: G
authors.initials: G
authors.lastname: Caliendo
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009636:Norbornanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000187:drug effects*; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000187:drug effects*; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry / Q000187:drug effects*; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000737:chemistry / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D009636:Norbornanes; 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; D018490:Serotonin Agents; D044282:Receptor, Serotonin, 5-HT1A