New Tacrine−Huperzine A Hybrids (Huprines):  Highly Potent Tight-Binding Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's Disease

• Published in: Journal of medicinal chemistry Vol. 43; no. 24; pp. 4657 - 4666
• Main Authors: Camps, Pelayo, El Achab, Rachid, Morral, Jordi, Muñoz-Torrero, Diego, Badia, Albert, Baños, Josep Eladi, Vivas, Nuria María, Barril, Xavier, Orozco, Modesto, Luque, Francisco Javier
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 30-11-2000
• Subjects: Acetylcholinesterase - metabolism; Alkaloids; Alzheimer Disease - drug therapy; Animals; Biological and medical sciences; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - pharmacology; Butyrylcholinesterase - metabolism; Cattle; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Humans; In Vitro Techniques; Male; Medical sciences; Mice; Models, Molecular; Neuromuscular Junction - drug effects; Neuromuscular Junction - physiology; Neuromuscular Nondepolarizing Agents - pharmacology; Neuropharmacology; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Rats; Rats, Sprague-Dawley; Sesquiterpenes - chemistry; Stereoisomerism; Structure-Activity Relationship; Tacrine - chemistry; Tubocurarine - pharmacology; Intraperitoneal administration; Enantioselectivity; Alzheimer disease; Nitrogen heterocycle; Molecular dynamics method; Esterases; Thermodynamic cycle; Reversible reaction; Selectivity; Acetylcholinesterase; Blood brain barrier; Modeling; Racemic; Ex vivo; Structure activity relation; Molecular model; Aromatic compound; Chemical synthesis; Halogen Organic compounds; Enantiomer(-); Human; Enzyme; Enzyme inhibitor; Inhibitor enzyme complex; Tetracyclic compound; In vitro; Carboxylic ester hydrolases; Animal; Binding energy; Hydrolases; Thermodynamic properties
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000980y

Several new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives (tacrine−huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (−)-20, rac-26, (−)-26, rac-30, (−)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (−)-20, (−)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438−871-fold higher than for BChE. Several hybrid compounds, specially (−)-20 and (−)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme−inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (−)-20 and (−)-30 and showed their ability to cross the blood−brain barrier. Molecular modeling simulations of the AChE−inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.