Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

• Published in: Journal of medicinal chemistry Vol. 42; no. 17; pp. 3227 - 3242
• Main Authors: Camps, Pelayo, El Achab, Rachid, Görbig, Diana Marina, 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 26-08-1999
• Subjects: Acetylcholinesterase - chemistry; Alkaloids; Animals; Binding Sites; Biological and medical sciences; Cholinergic system; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Diaphragm - drug effects; Diaphragm - innervation; Diaphragm - physiology; huperzine A; In Vitro Techniques; Male; Medical sciences; Models, Molecular; Muscle Contraction - drug effects; Neuromuscular Junction - drug effects; Neuromuscular Junction - physiology; Neuropharmacology; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Phrenic Nerve - drug effects; Phrenic Nerve - physiology; 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 - chemical synthesis; Sesquiterpenes - chemistry; Sesquiterpenes - pharmacology; Stereoisomerism; Structure-Activity Relationship; Tacrine - analogs & derivatives; Tacrine - chemical synthesis; Tacrine - chemistry; Tacrine - pharmacology; Torpedo; Rat; Alzheimer disease; Nitrogen heterocycle; Central nervous system; Esterases; Acetylcholinesterase; Modeling; Racemic; Amine; Structure activity relation; Molecular model; Aromatic compound; Degenerative disease; Chemical synthesis; Tacrine; Enzyme; Rodentia; Enzyme inhibitor; Tetracyclic compound; In vitro; Carboxylic ester hydrolases; Vertebrata; Mammalia; Animal; Hydrolases; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980620z

Eleven new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [tacrine (THA)−huperzine A hybrids, rac-21−31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (−)-huperzine A]. The activity of some THA−huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27−31, (−)-28, and (−)-30], which are more active than (−)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (−)-huperzine A. Most of the tested compounds 19−31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA−huperzine A hybrids:  the 4-aminoquinoline subunit of (−)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (−)-huperzine A, in agreement with the absolute configurations of (−)-19 and (−)-huperzine A.