title: Unichiral 2-(2'-pyrrolidinyl)-1,4-benzodioxanes: the 2R,2'S diastereomer of the N-methyl-7-hydroxy analogue is a potent α4β2- and α6β2-nicotinic acetylcholine receptor partial agonist.
abstract: A series of unichiral 7-substituted 2-(1'-methyl-2'-pyrrolidinyl)-1,4-benzodioxanes were synthesized and tested for the affinity for the α4β2 and α7 central nicotinic receptors; the 2R,2'S diastereomer of the 7-OH analogue [(R,S)-7], unique in the series, has a high α4β2 affinity (12nM K(i)). N-Demethylation and configuration inversion of the stereocenters greatly weaken its α4β2 affinity, confirming that such a rigid molecule can be considered a new template for α4β2 ligands. Docking analysis showed how (R,S)-7 is capable of strongly and specifically interacting with the amino acidic counterpart of the α4β2 receptor binding site. Further pharmacological characterization demonstrated that (R,S)-7 also has a high affinity for the α6β2 receptor, and in vitro functional tests indicated that it is a potent α4β2 and α6β2 partial agonist, with modest affinity and potency for the α3β4 receptor. Comparison with varenicline, a well-known nicotinic partial agonist used as a smoking cessation aid, interestingly reveals similar nicotinoid profiles.
authors.affiliation: Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università degli Studi di Milano, Milano, Italia.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
authors.forename: Matteo
authors.initials: M
authors.lastname: Binda
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.forename: Luca
authors.initials: L
authors.lastname: Pucci
authors.forename: Francesco
authors.initials: F
authors.lastname: Pistillo
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
mesh_terms: D000818:Animals; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C569671:2-(1'-methyl-2'-pyrrolidinyl)-7-hydroxy-1,4-benzodioxane; D004146:Dioxanes; D018722:Nicotinic Agonists; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; C403531:nicotinic receptor alpha4beta2; D004298:Dopamine