Departament de Farmacologia i Química Terapèutica

Research lines

Design and synthesis of novel disease-modifying anti-Alzheimer compounds

 

Alzheimer’s disease (AD) affects over 35 million people worldwide and with the current demographics its prevalence will increase 2-3-fold at the middle of this century. The situation is even more dramatic if we consider that drugs addressing the underlying mechanisms of the disease are not yet available.

Dual binding site inhibitors of the enzyme acetylcholinesterase (AChE) are compounds which can simultaneously interact with both the active site of the enzyme, at the bottom of a 20 Å-long  gorge, and with a second binding site, the so-called peripheral site, at the entrance of the gorge. This double blockade is very interesting for the treatment of AD. Blockade of the active site results in the inhibition of the hydrolysis of the neurotransmitter acetylcholine, which allows the compensation of the central cholinergic deficit responsible for the simptomatology of AD. More interestingly, blockade of the peripheral site results in the inhibition of the aggregation of the beta-amyloid peptide, the key process triggering the neurodegenerative cascade of AD, which in a great part seems to be mediated by an initial interaction between beta-amyloid and the peripheral site of AChE.

In our research group, we are designing and synthesizing different families of dual binding site AChE inhibitors by connection, through linkers of appropriate length, of structural moieties suited to interact with the two enzyme binding sites, as multipotent compounds with potential to alleviate the cognitive decline of AD patients, and more interestingly, to positively modify the natural course of the disease.

 

 

Figure 1. Structure, dual site binding to human AChE and in vitro pharmacological profile of one of the dual binding site AChE inhibitors developed in our research group

Design and synthesis of novel aminoquinoline chemotherapeutic agents

Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense or T. brucei rhodesiense, and malaria, caused by Plasmodium species, constitute major protozoan parasitic diseases in developing countries, where they cause over 30,000 and 1-3 million deaths annually, respectively. Despite their mortality, conventional treatments are inadequate mainly due to toxicity issues and to the emergence of resistance, especially in the case of antimalarials such as chloroquine. In this light, there is a desperate need for new and better drugs.

Huprines, developed in our group as anticholinesterase agents have been found to be potent trypanocidal agents and some of them also moderately potent against a chloroquine resistant Plasmodium falciparum strain, which makes them interesting lead compounds with dual trypanocidal-antimalarial activity. Worthy of note, this dual profile could result in cost-effective treatments, of special relevance in developing countries, where malaria and HAT are endemic. The huprines with a dual profile are among the least potent as AChE inhibitors, a positive feature which should result in a lower incidence of cholinergic side effects. However, the difference between the active dose against Plasmodium and their cytotoxic dose is rather small, thereby making it necessary the optimization of these leads.

 

 Figure 2. Structure and dual trypanocidal-antiplasmodial profile of some huprines.

  

Recent research projects

 

Title of the project / contract: Nuevos compuestos de potencial interés industrial.

Financing Firm/administration: Comisión Interministerial de Ciencia y Tecnología, CICYT (CTQ2011-22433)

Main researcher: Pelayo Camps

 

Title of the project / contract: Química Farmacéutica

Financing Firm/administration: Agència de Gestió d'Ajuts Universitaris i de Recerca. Generalitat de Catalunya. AGAUR (2009SGR1396)

Main researcher: Pelayo Camps

 

Title of the project / contract: Fons Prova de Concepte FPC-2010-19

Financing Firm/administration: Fundació Bosch i Gimpera – Barcelona Knowledge Campus (BKC)

Main researcher: Diego Muñoz-Torrero

 

Title of the project / contract: Colaboración entre la UB y Genoma España para el desarrollo de compuestos modificadores de la enfermedad de Alzheimer así como las acciones de desarrollo, de explotación industrial y de comercialización de la patente ES201000016

Financing Firm/administration: Fundación para el desarrollo de la investigación en genómica y proteómica (Genoma España)

Main researcher: Diego Muñoz-Torrero

 

Recent publications

Galdeano, C.; Viayna, E.; Sola, I.; Formosa, X.; Camps, P.; Badia, A.; Clos, M. V.; Relat, J.; Ratia, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Salmona, M.; Minguillón, C.; González-Muñoz, G. C.; Rodríguez-Franco, M. I.; Bidon-Chanal, A.; Luque, F. J.; Muñoz-Torrero, D. Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer’s and prion diseases. J. Med. Chem. 2012, 55, 661-669.

 

Muñoz-Torrero, D.; Pera, M.; Relat, J.; Ratia, M.; Galdeano, C.; Viayna, E.; Sola, I.; Formosa, X.; Camps, P.; Badia, A.; Clos, M. V. Expanding the multipotent profile of huprine-tacrine heterodimers as disease-modifying anti-Alzheimer agents. Neurodegener. Dis. 2012, in press (DOI: 10.1159/000333225).

 

Defaux, J.; Sala, M.; Formosa, X.; Galdeano, C.; Taylor, M. C.; Alobaid, W. A. A.; Kelly, J. M.; Wright, C. W.; Camps, P.; Muñoz-Torrero, D. Huprines as a new family of dual acting trypanocidal-antiplasmodial agents. Bioorg. Med. Chem. 2011, 19, in press (DOI 10.1016/j.bmc.2011.01.028).

 

Viayna, E.; Gómez, T.; Galdeano, C.; Ramírez, L.; Ratia, M.; Badia, A.; Clos, M. V.; Verdaguer, E.; Junyent, F.; Camins, A.; Pallàs, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Arce, M. P.; Rodríguez-Franco, M. I.; Bidon-Chanal, A.; Luque, F. J.; Camps, P.; Muñoz-Torrero, D. Novel huprine derivatives with inhibitory activity toward beta-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates. ChemMedChem 2010, 5, 1855-1870.

 

Muñoz-Torrero, D.; Camps, P.; Gómez, T.; Viayna, E.; Galdeano, C. Compuestos multifuncionales modificadores de la enfermedad de Alzheimer para el tratamiento de esta enfermedad. Patent P201000016 (PCT/ES2010/070862) Date of priority: 2010 Main institution: Universitat de Barcelona

 

Galdeano, C.; Viayna, E.; Arroyo, P.; Bidon-Chanal, A.; Blas, J. R.; Muñoz-Torrero, D.; Luque, F. J.

Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-Alzheimer agents Curr. Pharm. Des. 2010, 16, 2818-2836.

 

Ratia, M.; Giménez-Llort, L.; Camps, P.; Muñoz-Torrero, D.; Clos, M. V.; Badia, A. Behavioural effects and regulation of PKC alpha and MAPK by huprine X in middle aged mice. Pharmacol. Biochem. Behav. 2010, 95, 485-493.

 

Hedberg, M. M.; Clos, M. V.; Ratia, M.; Gonzalez, D.; Unger Lithner, C.; Camps, P.; Muñoz-Torrero, D.; Badia, A.; Giménez-Llort, L.; Nordberg, A. Effect of huprine X on Abeta, synaptophysin and alpha7 neuronal nicotinic acetylcholine receptors in the brain of 3xTg-AD and APPswe transgenic mice. Neurodegener. Dis. 2010, 7, 379-388.

 

Camps, P.; Formosa, X. ; Galdeano, C.; Gómez, T.; Muñoz-Torrero, D.; Ramírez, L.; Viayna, E.; Gómez, E.; Isambert, N.; Lavilla, R.; Badia, A.; Clos, M. V.; Bartolini, M.; Mancini, F.; Andrisano, V.; Bidon-Chanal, A.; Huertas, O.; Dafni, T.; Luque, F. J. Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates. Chem.-Biol. Interact. 2010, 187, 411-415.

 

Camps, P.; Formosa, X. ; Galdeano, C.; Muñoz-Torrero, D.; Ramírez, L.; Gómez, E.; Isambert, N.; Lavilla, R.; Badia, A.; Clos, M. V.; Bartolini, M.; Mancini, F.; Andrisano, V.; Arce, M. P.; Rodríguez-Franco, M. I.; Huertas, O.; Dafni, T.; Luque, F. J. Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and ²-amyloid-directed anti-Alzheimer compounds. J. Med. Chem. 2009, 52, 5365-5379.

 

Oluwafemi, A.J.; Okanla, E.O.; Camps, P.; Muñoz-Torrero, D.; Mackey, Z.B.; Chiang, P.K.; Seville, S.; Wright, C.W. Evaluation of cryptolepine and huperzine derivatives as lead compounds towards new agents for the treatment of human african trypanosomiasis. Nat. Prod. Commun. 2009, 4, 193-198.

 

Muñoz-Torrero, D. Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer's disease. Curr. Med. Chem. 2008, 15, 2433-2455.

 

Camps, P.; Formosa, X. ; Galdeano, C.; Gómez, T.; Muñoz-Torrero, D.; Scarpellini, M.; Viayna, E.; Badia, A.; Clos, M.V.; Camins, A.; Pallàs, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Estelrich, J.; Lizondo, M.; Bidon-Chanal, A.; Luque, F. J. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. J. Med. Chem. 2008, 51, 3588-3598.

 

Muñoz-Torrero, D.; Camps, P. Huprines for Alzheimer's disease drug development. Expert Opin. Drug Discovery 2008, 3, 65-81.

 

 

Current collaborations

Dr. F. Javier Luque, Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona (Spain)

Drs. Albert Badia and M. Victòria Clos, Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona (Spain)

Drs. Mercè Pallàs and Antoni Camins, Departament de Farmacologia i Química Terapèutica, Facultat de Farmàcia, Universitat de Barcelona (Spain)

Dr. Rodolfo Lavilla, Departament de Farmacologia i Química Terapèutica, Facultat de Farmàcia, Universitat de Barcelona (Spain)

Drs. Vincenza Andrisano, Manuela Bartolini, and Francesca Mancini, Dipartimento di Scienze Farmaceutiche, Università di Bologna (Italy)

Dr. Mª Isabel Rodríguez-Franco, Instituto de Química Médica (CSIC), Madrid (Spain)

Dr. Florian Nachon, Toxicology Department, Enzymology Unit, Centre de Recherches du Service de Santé des Armées (France)

Dr. John  M. Kelly, London School of Hygiene and Tropical Medicine (United Kingdom)

Dr. Colin W. Wrigth, Bradford School of Pharmacy (United Kingdom)

Drs. Mario Salmona and Luisa Diomede, Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan (Italy)

 

Current group members

 

Dr. Diego Muñoz-Torrero                 Associate Professor      dmunoztorrero@ub.edu

Carles Galdeano                             PhD student                cargalcan@hotmail.com

Elisabet Viayna                              PhD student                elisabet.viayna@gmail.com

Irene Sola                                      PhD student                irenesola87@hotmail.com

Ornella Di Pietro                             PhD student                ornella.dipietro@libero.it

Antonio Viayna                               Collaboration fellow     anthony_1221@hotmail.com