title: Synthesis, in vitro and in vivo pharmacological evaluation of serotoninergic ligands containing an isonicotinic nucleus.
abstract: Isonicotinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors were evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to play critical roles in affinity for serotoninergic receptors and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(3-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)propyl)isonicotinamide (4s) with Ki = 0.130 nM, was the most active and selective derivative for the 5-HT1A receptor compared to other serotoninergic, dopaminergic and adrenergic receptors. Compound 4o, instead, showed 5-HT2A affinity values in subnamolar range. Moreover, the compounds having better affinity and selectivity binding profile towards 5-HT1A and 5-HT2A receptors were selected in order to be tested by in vitro and in vivo assays to determine their functional activity.
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy. Electronic address: fefiorin@unina.it.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Fiorino
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ciano
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Magli
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Severino
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corvino
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Perissutti
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Frecentese
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Vaio
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Izzo
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Capasso
authors.affiliation: Dipartimento di Scienze Mediche, Chirurgiche e Neuroscienze Università di Siena, Via delle Scotte, 6, 53100, Siena, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Massarelli
authors.affiliation: Dipartimento di Scienze Mediche, Chirurgiche e Neuroscienze Università di Siena, Via delle Scotte, 6, 53100, Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nencini
authors.affiliation: Dipartimento di Scienze Mediche, Chirurgiche e Neuroscienze Università di Siena, Via delle Scotte, 6, 53100, Siena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Rossi
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 20-093 Lublin, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kędzierska
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 20-093 Lublin, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Orzelska-Gòrka
authors.affiliation: Department of Biochemistry, Medical University of Warsaw, 02-097 Warszawa, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Bielenica
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Santagada
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Caliendo
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009536:Niacinamide / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*
chemical_list: D008024:Ligands; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D044282:Receptor, Serotonin, 5-HT1A; D000077489:Piperazine; D009536:Niacinamide; C027681:isonicotinamide
keywords: 5-HT(1A); 5-HT(2A) and 5-HT(2C) ligands; Behavioural tests; Binding assays; In vitro assay; Isonicotinamide derivatives