title: Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype.
abstract: We report the design, synthesis and pharmacological screening of a group of analogues of anabaseine 2, a naturally occurring unselective nicotinic agonist. The novel nAChR ligands 5-15 were planned following a molecular modeling analysis which suggested the replacement of the pyridine ring of 2 with a 3-substituted benzene ring as a means to gain selectivity for the α3β4 nAChR subtype. Overall, from binding experiments, the synthesized compounds showed high values of α3β4 affinity and α3β4 vs α4β2 selectivity, although they poorly discriminated the homomeric α7 subtype. The three analogues 6, 12 and 13 were also evaluated in electrophysiological assays, and 12 [6-(3-iodophenyl)-2,3,4,5-tetrahydropyridine] emerged as a rather interesting nicotinic ligand. Indeed, in addition to a noteworthy affinity (Ki = 4.7 nM) for the α3β4 subtype and to an excellent α3β4 vs α4β2 subtype selectivity (806-fold), compound 12 selectively activated the α3β4 nAChR (EC50 = 7.4 μM) while eliciting a negligible response at the α7 subtype and no effect at the α4β2 subtype.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Matera
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Quadri
authors.affiliation: I.R.C.C.S. Neuromed, Istituto Neurologico Mediterraneo, Via Atinese 18, 86077 Pozzilli Isernia, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Sciaccaluga
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Diego Yuri
authors.initials: DY
authors.lastname: Pomè
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: Francesca
authors.initials: F
authors.lastname: Fasoli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
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: 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: 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 L. Mangiagalli 25, 20133 Milano, Italy. Electronic address: clelia.dallanoce@unimi.it.
authors.forename: Clelia
authors.initials: C
authors.lastname: Dallanoce
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
mesh_terms: D000691:Anabasine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D011725:Pyridines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C091713:anabaseine; D000691:Anabasine; C023666:pyridine
keywords: Anabaseine-related derivatives; Binding affinity; Design; Functional activity/selectivity; Molecular modeling; Neuronal nicotinic acetylcholine receptors; α3β4 nicotinic ligands