Synthesis of novel classes of acetylcholinesterase inhibitors for the treatment and prevention of Alzheimer's disease
Research Interests
Our research interest is focused on the development of new reversible high affinity inhibitors of acetylcholinesterase able to cross the blood brain barrier, which can be useful to treat the symptoms and to delay and prevent the neurodegenerative process associated with Alzheimer's disease (AD).
Synthesis of huprines, a novel class of high affinity acetylcholinesterase inhibitors:
Starting from two known models of reversible acetylcholinesterase inhibitors (AChEIs), such as tacrine, the first AChEI to be commercialized for the treatment of AD, and (-)-huperzine A, a natural product exhibiting a potent and selective AChE inhibitory activity, and taking advantage of the fact that the binding sites of these lead compounds within the active site of the enzyme AChE are close and partially overlap, we designed through a conjunctive approach a new structural family of AChEIs which could simultaneously occupy both binding zones, thereby increasing their affinity for the enzyme. Thus, by combination in the same molecule of the 4-aminoquinoline moiety of the model tacrine and the carbobicyclic moiety of the model (-)-huperzine A we designed the so-called huprines or tacrine-huperzine A hybrids.
We have developed a straighforward synthetic sequence to gain access to huprines in racemic form, as well as a chromatographic resolution methodology which allows the separation of enantiopure (-)-huprines, the eutomers in this structural family of AChEIs, from the dextrorotatory enantiomers. Molecular modeling studies and 3D X-ray diffraction analysis have confirmed the extended binding of huprines within the active site of AChE, what accounts for their extremely high affinity (KI around 30 pM in some cases), potency (subnanomolar IC50 values), and selectivity of inhibition of AChE, being these compounds clearly superior to the commercialized AChEIs. The outstanding pharmacological profile of huprines is complemented by their ability to cross the blood brain barrier, their tight-binding character, and particularly by their neuroprotective effect though NMDA receptor antagonism, what makes these compounds promising drug candidates for the treatment and prevention of AD. While further development of the most interesting huprines is awaiting partnering, current efforts are being directed toward the synthesis of new rationally designed huprines with even improved affinity, and particularly of huprine- and tacrine-based heterodimers as dual binding site acetylcholinesterase inhibitors, which can interact simultaneously wiht both the active and the peripheral binding sites of the enzyme.
Recent papers
Camps, P.; El Achab, R.; Font-Bardia, M.; Görbig, D.; Morral, J.; Muñoz-Torrero, D.; Solans, X.; Simon, M. "Easy Synthesis of 7-Alkylbicyclo[3.3.1]non-6-en-3-ones by Silica Gel-Promoted Fragmentation of 3-Alkyl-2-oxaadamant-1-yl Mesylates", Tetrahedron 1996, 52, 5867-5880. PDF
Badia, A.; Baños, J.E.; Camps, P.; Contreras, J.; Görbig, D.M.; Muñoz-Torrero, D.; Simon, M.; Vivas, N.M. "Synthesis and Evaluation of Tacrine-Huperzine A Hybrids as Acetylcholinestrase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease", Bioorganic and Medicinal Chemistry 1998, 6, 427-440.PDF
Camps, P.; Contreras, J.; Font-Bardia, M.; Morral, J.; Muñoz-Torrero, D.; Solans, X. "Enantioselective Synthesis of Tacrine-Huperzine A Hybrids. Preparative Chiral MPLC Separation of Their Racemic Mixtures and Absolute Configuration Assignments by X-Ray Diffraction Analysis", Tetrahedron: Asymmetry 1998, 9, 835-849.PDF
Camps, P.; El Achab, R.; Görbig, D.M.; Morral, J.; Muñoz-Torrero,
D.; Badia, A.; Baños, J. E.; Vivas, N.M.; Barril, X.; Orozco,
M.; Luque, F.J. "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",
Journal of Medicinal Chemistry 1999, 42, 3227-3242.PDF
Camps, P.; Cusack, B.; Mallender, W.D.; El Achab, R.; Morral, J.; Muñoz-Torrero, D.; Rosenberry, T.L. "Huprine X is a Novel High Affinity Inhibitor of Acetylcholinesterase that is of Interest for the Treatment of Alzheimer's Disease", Molecular Pharmacology 2000, 57, 409-417. PDF
Camps, P.; El Achab, R.; Morral, J.; Muñoz-Torrero, D.; Badia, A.; Baños, J.E.; Vivas, N.M.; Barril, X.; Orozco, M.; Luque, F.J. "New Tacrine-Huperzine A Hybrids (Huprines): Highly Potent Tight-Binding Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's Disease", Journal of Medicinal Chemistry 2000, 43, 4657-4666.PDF
Ros, E.; Aleu, J.; Gómez de Aranda, I.; Muñoz-Torrero, D.; Camps, P.; Badia, A.; Marsal, J. ; Solsona, C. "The Pharmacology of Novel Acetylcholinesterase Inhibitors, ( )-Huprines Y and X, on the Torpedo Electric Organ", European Journal of Pharmacology 2001, 421, 77-84. PDF
Camps, P.; Muñoz-Torrero, D. "Tacrine-Huperzine A Hybrids (Huprines): A New Class of Highly Potent and Selective Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's Disease", Mini Reviews in Medicinal Chemistry 2001, 1, 163-174. PDF
Camps, P.; Gómez, E.; Muñoz-Torrero, D.; Badia, A.; Vivas, N.M.; Barril, X.; Orozco, M.; Luque, F.J. "Synthesis, in Vitro Pharmacology and Molecular Modeling of syn-Huprines as Acetylcholinesterase Inhibitors", Journal of Medicinal Chemistry 2001, 44, 4733-4736. PDF
Camps, P.; Gómez, E.; Muñoz-Torrero, D.; Arnó, M. "On the Regioselectivity of the Friedländer Reaction Leading to Huprines: Stereospecific Acid-Promoted Isomerization of syn-Huprines to their anti-Regioisomers", Tetrahedron: Asymmetry 2001, 12, 2909-2914.PDF
Camps, P.; Muñoz-Torrero, D. "Cholinergic Drugs in Pharmacotherapy of Alzheimer's Disease", Mini Reviews in Medicinal Chemistry 2002, 2, 11-25. PDF
Dvir, H.; Wong, D. M.; Harel, M.; Barril, X.; Orozco, M.; Luque, F. J.; Muñoz-Torrero, D.; Camps, P. Rosenberry, T. L.; Silman, I.; Sussman, J. L. "3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates", Biochemistry 2002, 41, 2970-2981. PDF
Canudas, A.M.; Pubill, D.; Sureda, F.X.; Verdaguer, E.; Camps, P.; Muñoz-Torrero, D.; Jiménez, A.; Camins, A.; Pallàs, M. "Neuroprotective Effects of ( )-Huprine Y on in Vitro and in Vivo Models of Excitotoxicity Damage", Experimental Neurology 2003, 180, 123-130. PDF
Alcalá, M.M.; Vivas, N.M.; Hospital, S.; Camps, P.; Muñoz-Torrero, D.; Badia, A. "Characterisation of the anticholinesterase activity of two new tacrine huperzine A hybrids", Neuropharmacology 2003, 44, 749-755. PDF
Camps, P.; Gómez, E.; Muñoz-Torrero, D.; Font-Bardia, M.; Solans, X. "Synthesis of diastereomeric 13-amido-substituted huprines as potential high affinity acetylcholinesterase inhibitors", Tetrahedron 2003, 59, 4143-4151.PDF
Camps, P.; Gómez, E.; Muñoz-Torrero, D. "Synthesis of 13-acylamino-huprines: different behavior of diastereomeric 13-methanesulfonamido-huprines on PPA-mediated hydrolysis, Tetrahedron 2004, 60, 5423 5431.PDF
Jordá, E.G.; Verdaguer, E.; Jiménez, A.; Canudas, A.M.; Rimbau, V.; Camps, P.; Muñoz-Torrero, D.; Camins, A.; Pallàs, M. "(±)-Huprine Y, ( )-huperzine A and tacrine do not show neuroprotective properties in an apoptotic model of neuronal cytoskeletal alteration", Journal of Alzheimer's Disease 2004, 6, 577 583.
Camps, P.; Formosa, X..; Muñoz-Torrero, D.; Petrignet, J.; Badia, A.; Clos, M. V. "Synthesis and pharmacological evaluation of huprine-tacrine heterodimers: Subnanomolar dual binding site acetylcholinesterase inhibitors", Journal of Medicinal Chemistry 2005, 48, 1701-1704. . PDF
Alcalá, M. M.; Maderuelo, A.; Vivas, N. M.; Camps, P.; Muñoz-Torrero,
D.; Clos, M. V.; Badia, A. "Effects of (±)-huprine Y and
(±)-huprine Z, two new anticholinesterasic drugs, on muscarinic
receptors", Neuroscience Letters 2005, 379, 106-109.
.PDF
Current collaborations
Prof. Dr. Terrone L. Rosenberry, Department of Pharmacology and Program
in Neurosciences, Mayo Clinic (Jacksonville, USA)
Prof. Dr. Joel L. Sussman, Department of Structural Biology, Weizmann
Institute of Science (Rehovot, Israel)
Prof. Dr. F. Javier Luque, Departament de Físico-Química,
Universitat de Barcelona (Spain)
Prof. Dr. Albert Badia and Dr. M. Victòria Clos, Departament
de Farmacologia i Terapèutica, Universitat Autònoma de
Barcelona (Spain)
Dr. Carles Solsona, Departament de Biologia Cel.lular i Anatomia Patològica,
Universitat de Barcelona (Spain)
Dr. Mercè Pallàs and Dr. Antoni Camins, Unitat de Farmacologia
i Farmacognòsia, Universitat de Barcelona (Spain)
| Prof. Dr. Pelayo Camps
camps@ub.edu |
|
||
|
|
|
||