title: Synthesis and Pharmacological Evaluation of α4β2 Nicotinic Ligands with a 3-Fluoropyrrolidine Nucleus.
abstract: Nicotinic acetylcholine receptors (nAChRs) play an important role in many central nervous system disorders such as Alzheimer's and Parkinson's diseases, schizophrenia, and mood disorders. The α(4)β(2) subtype has emerged as an important target for the early diagnosis and amelioration of Alzheimer's disease symptoms. Herein we report a new class of α(4)β(2) receptor ligands characterized by a basic pyrrolidine nucleus, the basicity of which was properly decreased through the insertion of a fluorine atom at the 3-position, and a pyridine ring carrying at the 3-position substituents known to positively affect affinity and selectivity toward the α(4)β(2) subtype. Derivatives 3-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-5-(phenylethynyl)pyridine (11) and 3-((4-fluorophenyl)ethynyl)-5-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)pyridine (12) were found to be the most promising ligands identified in this study, showing good affinity and selectivity for the α(4)β(2) subtype and physicochemical properties predictive of a relevant central nervous system penetration.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano (Italy).
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano (Italy). andrea.pinto@unimi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata 98168, Messina (Italy).
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, CNR, Istituto di Neuroscienze, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milan (Italy).
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, CNR, Istituto di Neuroscienze, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milan (Italy).
authors.forename: Francesca
authors.initials: F
authors.lastname: Fasoli
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano (Italy).
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano (Italy).
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
mesh_terms: D000818:Animals; D005461:Fluorine / Q000737:chemistry*; D008297:Male; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism
chemical_list: D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D005461:Fluorine; C032519:pyrrolidine
keywords: 3-fluoropyrrolidines; nicotinic receptors; selectivity; structure-activity relationships; α4β2 ligands