title: Quinolizidinyl derivatives of bi- and tricyclic systems as potent inhibitors of acetyl- and butyrylcholinesterase with potential in Alzheimer's disease.
abstract: On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e.g. 15: IC50 versus BChE=0.15 μM; SI=47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e.g. 46: IC50 versus AChE=0.35 μM; SI=0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer's disease, and may, therefore, represent hits for the development of interesting single-entity multi-target drugs.
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, V.le Benedetto XV, 3, I-16132 Genova, Italy. bruno.tasso@unige.it
authors: B
authors: B
authors: Tasso
authors: M
authors: M
authors: Catto
authors: O
authors: O
authors: Nicolotti
authors: F
authors: F
authors: Novelli
authors: M
authors: M
authors: Tonelli
authors: I
authors: I
authors: Giangreco
authors: L
authors: L
authors: Pisani
authors: A
authors: A
authors: Sparatore
authors: V
authors: V
authors: Boido
authors: A
authors: A
authors: Carotti
authors: F
authors: F
authors: Sparatore
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D054837:Quinolizidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D054837:Quinolizidines; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase