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

Article English OPEN
Camps, Pelayo ; El Achab, Rachid ; Görbig, Diana Marina ; Morral-Cardoner, Jordi ; Muñoz-Torrero, Diego ; Badia, Albert ; Baños, Josep Eladi ; Vivas, Nuria María ; Barril, Xavier ; Orozco, Modesto ; Luque, Francisco Javier (1999)

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.
  • References (70)
    70 references, page 1 of 7

    (1) Davies, P.; Malony, A. J. F. Selective Loss of Central Cholinergic Neurons in Alzheimer's Disease. Lancet 1976, 2, 1403.

    (2) Perry, E. K.; Perry, R. H.; Blessed, G.; Tomlinson, B. E. Necropsy Evidence of Central Cholinergic Deficits in Senile Dementia. Lancet 1977, 1, 189.

    (3) White, P.; Goodhard, M. J.; Keet, J. K.; Hiley, C. R.; Carrasio, L. H.; William, I. E. I. Neocortical Cholinergic Neurons in Elderly People. Lancet 1977, 1, 668-671.

    (4) Reisine, T. D.; Yamamura, H. I.; Bird, E. D.; Spokes, E.; Enna, S. J. Pre- and Postsynaptic Neurochemical Alterations in Alzheimer's Disease. Brain Res. 1978, 159, 477-481.

    (5) Davies, P. Neurotransmitter-Related Enzymes in Senile Dementia of the Alzheimer Type. Brain Res. 1979, 171, 319-327.

    (6) Hollander, E.; Mohs, R. C.; Davis, K. L. Cholinergic Approaches to the Treatment of Alzheimer's Disease. Br. Med. Bull. 1986, 42, 97-100.

    (7) Hershenson, F. M.; Moos, W. H. Drug Development for Senile Cognitive Decline. J. Med. Chem. 1986, 29, 1125-1130.

    (8) Davis, K. L.; Powchik, P. Tacrine. Lancet 1995, 345, 625-630.

    (9) Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K. Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]- piperidine Hydrochloride and Related Compounds. J. Med. Chem. 1995, 38, 4821-4829.

    (10) Prous, J.; Rabasseda, X.; Castan˜ er, J. SDZ-ENA-713 Cognition Enhancer Acetylcholinesterase Inhibitor. Drugs Future 1996, 19, 656-658.

  • Bioentities (2)
    1acj Protein Data Bank
    1vot Protein Data Bank
  • Metrics
    views in OpenAIRE
    views in local repository
    downloads in local repository

    The information is available from the following content providers:

    From Number Of Views Number Of Downloads
    University of Huddersfield Repository - IRUS-UK 0 153
Share - Bookmark