title: Chemistry and Pharmacology of a Series of Unichiral Analogues of 2-(2-Pyrrolidinyl)-1,4-benzodioxane, Prolinol Phenyl Ether, and Prolinol 3-Pyridyl Ether Designed as α4β2-Nicotinic Acetylcholine Receptor Agonists.
abstract: Some unichiral analogues of 2R,2'S-2-(1'-methyl-2'-pyrrolidinyl)-7-hydroxy-1,4-benzodioxane, a potent and selective α4β2-nAChR partial agonist, were designed by opening dioxane and replacing hydroxyl carbon with nitrogen. The resulting 3-pyridyl and m-hydroxyphenyl ethers have high α4β2 affinity and good subtype selectivity, which get lost if OH is removed from phenyl or the position of pyridine nitrogen is changed. High α4β2 affinity and selectivity are also attained by meta hydroxylating the 3-pyridyl and the phenyl ethers of (S)-N-methylprolinol and the phenyl ether of (S)-2-azetidinemethanol, known α4β2 agonists, although the interaction mode of the aryloxymethylene substructure cannot be assimilated to that of benzodioxane. Indeed, the α4β2 and α3β4 functional tests well differentiate behaviors that the binding tests homologize: both the 3-hydroxyphenyl and the 5-hydroxy-3-pyridyl ether of N-methylprolinol are α4β2 full agonists, but only the latter is highly α4β2/α3β4 selective, while potent and selective partial α4β2 agonism characterizes the hydroxybenzodioxane derivative and its two opened semirigid analogues.
authors.affiliation: Dipartimento di Scienze Farmaceutiche "Pietro Pratesi", Università degli Studi di Milano , Via Mangiagalli 25, I-20133, Milano, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.affiliation: Dipartimento di Scienze Farmaceutiche "Pietro Pratesi", Università degli Studi di Milano , Via Mangiagalli 25, I-20133, Milano, Italy.
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
authors.affiliation: CNR, Istituto di Neuroscienze, and Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, Milano, I-20129, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.affiliation: CNR, Istituto di Neuroscienze, and Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, Milano, I-20129, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fasoli
authors.affiliation: Dipartimento di Scienze Farmaceutiche "Pietro Pratesi", Università degli Studi di Milano , Via Mangiagalli 25, I-20133, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ruggeri
authors.affiliation: Dipartimento di Scienze Farmaceutiche "Pietro Pratesi", Università degli Studi di Milano , Via Mangiagalli 25, I-20133, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.affiliation: Dipartimento di Scienze Farmaceutiche "Pietro Pratesi", Università degli Studi di Milano , Via Mangiagalli 25, I-20133, Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Binda
authors.affiliation: CNR, Istituto di Neuroscienze, and Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, Milano, I-20129, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Mucchietto
authors.affiliation: I.R.C.C.S. Neuromed, Istituto Neurologico Mediterraneo, Via Atinese 18, I-86077, Pozzilli, Isernia, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Sciaccaluga
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum, Università di Bologna , Via Belmeloro 6, I-40126, Bologna, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.affiliation: I.R.C.C.S. Neuromed, Istituto Neurologico Mediterraneo, Via Atinese 18, I-86077, Pozzilli, Isernia, Italy.|Dipartimento di Fisiologia e Farmacologia, Università di Roma La Sapienza , Piazzale Moro 5, 00185 Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fucile
authors.affiliation: Dipartimento di Scienze Farmaceutiche "Pietro Pratesi", Università degli Studi di Milano , Via Mangiagalli 25, I-20133, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002460:Cell Line; D004146:Dioxanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009538:Nicotine / Q000737:chemistry / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C569671:2-(1'-methyl-2'-pyrrolidinyl)-7-hydroxy-1,4-benzodioxane; D004146:Dioxanes; D018722:Nicotinic Agonists; D010647:Phenyl Ethers; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine