title: Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization.
abstract: We designed, prepared and tested a set of structural analogs 1-4 as new hybrid compounds by incorporating, through a common alkyl chain of variable length, the pharmacophoric elements of N-n-alkyl nicotinium salts (non-α7 nicotinic acetylcholine receptors antagonists) and of 7-hydroxy-2-(aminomethyl)chromanes (dopaminergic D2 receptor agonists). The target compounds, which were assayed in binding experiments and electrophysiological, functional and Erk1/2 activation tests, essentially combined the pharmacological profiles of their individual receptor ligands. Among the studied derivatives, hybrid 2, one of the shortest homologs, in addition to the antagonist nicotinic profile similar to the other three congeners, behaved as a high affinity ligand at the investigated heteromeric nAChRs and as a low efficacy agonist at D2Rs. These bifunctional derivatives represent novel pharmacological tools in the study of nicotine addiction.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Matera
authors.affiliation: Consiglio Nazionale delle Ricerche (CNR), Istituto di Neuroscienze, Via Vanvitelli 32, 20129 Milano, Italy; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pucci
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Viale Europa 11, 25123 Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiorentini
authors.affiliation: I.R.C.C.S. Neuromed, Istituto Neurologico Mediterraneo, Via Atinese 18, 86077 Pozzilli, Isernia, Italy; Dipartimento di Fisiologia e Farmacologia, Università di Roma La Sapienza, Piazzale A. Moro 5, 00185 Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fucile
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Viale Europa 11, 25123 Brescia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Missale
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.affiliation: Consiglio Nazionale delle Ricerche (CNR), Istituto di Neuroscienze, Via Vanvitelli 32, 20129 Milano, Italy; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Clementi
authors.affiliation: Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze - Sezione di Fisiologia e Neuroscienze, Università degli Studi di Modena e Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Zoli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
authors.affiliation: Consiglio Nazionale delle Ricerche (CNR), Istituto di Neuroscienze, Via Vanvitelli 32, 20129 Milano, Italy; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy. Electronic address: c.gotti@in.cnr.it.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. Electronic address: clelia.dallanoce@unimi.it.
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
mesh_terms: D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors*
chemical_list: D018491:Dopamine Agonists; D018733:Nicotinic Antagonists; D017448:Receptors, Dopamine D2; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Bifunctional ligands; Binding affinity; D(2) receptors; Dopamine release; Electrophysiological assays; Erk phosphorylation tests; Neuronal nicotinic acetylcholine receptors; Nicotine addiction; α4β2 nAChRs