Plenary Lecture

Plenary Lecture

Tacripyrines, the First Tacrine-Dihydropyridine Hybrids, as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease

Associate Professor Maria do Carmo Carreiras
Co-authors: J. Marco-Contelles, F. Javier Luque, R. Leon, A. Samadi
iMed.UL, Research Institute for Medicines and Pharmaceutical Sciences
Faculty of Pharmacy, University of Lisbon
Av. Forcas Armadas, 1600-083 Lisbon

Abstract: Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are aimed to develop a multitarget therapeutic strategy to confront Alzheimer's disease (AD). Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 15 nM) is associated to a 30.7 8.6% inhibition of the proaggregating action of AChE on the A and a moderate inhibition of A self-aggregation (34.9 5.4%). Molecular modelling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11.

Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the BBB, emerging as lead candidates for treating AD.

Brief Biography of the Speaker:
Maria do Carmo Carreiras received her degree in Pharmacy from University of Lisbon in 1977, her Master Sci. in Organic chemistry from University Nova of Lisbon in 1987, and her Ph.D. in Pharmaceutical chemistry from University of Lisbon in 1989 (with honours). In 1985 she was a fellow at the Institut de Chimie des Substances Naturelles (CNRS), Gif-sur-Yvette, France, working under the direction of Prof. Henry-Philippe Husson. From 1986 to 1988 she was a Ph D student at Instituto de Quimica Organica General (IQOG), Consejo Superior de Investigaciones Cientificas of Madrid, working under direction of Prof. Benjamin Rodriguez.
From 1989 to 2006 she was Assistant Professor at the Faculty of Pharmacy, University of Lisbon. In 2006 she was appointed Associate Professor. She has been involved in teaching organic chemistry, heterocyclic chemistry and medicinal chemistry at the graduate and post-graduate level. From 1997 to 2004, in different periods, she was Visiting Professor at the IQOG, in Madrid, working under direction of Prof. Marco-Contelles. In 2005 she was Invited Professor at the Faculty of Sciences, University of Picardie Jules Verne, Amiens, France.
She is a member of the COST D34 Action in the frame of the project Molecular Targeting and Drug Design in Neurological and Bacteriological Diseases.
Her research interests involve the rational design of cholinesterase inhibitors as well as multitarget compounds for Alzheimer's disease.



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