Neuroprotective effects of the multitarget agent AVCRI104P3 in brain of middle-aged mice

Molecular factors involved in neuroprotection are key in the design of novelmultitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Abeta aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3beta, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3beta in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementi

Clock/Sleep-Dependent Learning and Memory in Male 3xTg-AD Mice at Advanced Disease Stages and Extrinsic Effects of Huprine X and the Novel Multitarget Agent AVCRI104P3

A new hypothesis highlights sleep-dependent learning/memory consolidation and regards the sleep-wake cycle as a modulator of beta-amyloid and tau Alzheimer's disease (AD) pathologies. Sundowning behavior is a common neuropsychiatric symptom (NPS) associated with dementia. Sleep fragmentation resulting from disturbances in sleep and circadian rhythms in AD may have important consequences on memory processes and exacerbate the other AD-NPS. The present work studied the effect of training time schedules on 12-month-old male 3xTg-AD mice modeling advanced disease stages. Their performance in two paradigms of the Morris water maze for spatial-reference and visual-perceptual learning and memory were found impaired at midday, after 4 h of non-active phase. In contrast, early-morning trained littermates, slowing down from their active phase, exhibited better performance and used goal-directed strategies and non-search navigation described for normal aging. The novel multitarget anticholinesterasic compound AVCRI104P3 (0.6 umol/kg, 21 days i.p.) exerted stronger cognitive benefits than its in vitro equipotent dose of AChEI huprine X (0.12 umol/kg, 21 days i.p.). Both compounds showed streamlined drug effectiveness, independently of the schedule. Their effects on anxiety-like behaviors were moderate. The results open a question of how time schedules modulate the capacity to respond to task demands and to assess/elucidate new drug effectiveness

Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene-bis(methylene)-linked bis(+)-huprines

We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypanocidal/anticholinesterase activity ratio

Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies

Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5bd have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5ad has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5ad, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities

Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads

Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene-bis(methylene)-linked bis(+)-huprines.

We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypanocidal/anticholinesterase activity ratio

Guia per desenvolupar la competència transversal. Comunicació escrita i oral

Les competències transversals són un aspecte clau en la formació dels estudiants de la Universitat. El Grup d'innovació docent de la Facultat de Veterinària ha desenvolupat unes guies amb l'objectiu d'estandarditzar l'ensenyament de les competències transversals al graus impartits a la Facultat, oferir eines i recursos a l'alumnat per ajudar-los a desenvolupar aquestes competències, i oferir eines i recursos al professorat per facilitar l'ensenyament i l'avaluació de les competències en el marc de les assignatures pròpies. La guia per desenvolupar la competència transversal de comunicació escrita i oral estableix tres nivells de domini i 7 indicadors d'aprenentatge que l'estudiant ha d'assolir de forma progressiva al llarg del grau. En acabar els estudis l'estudiant ha de demostrar que ha adquirit l'habilitat d'expressar-se oralment i per escrit en un registre científic

Synthesis and biological evaluation of N-cyanoalkyl-, Naminoalkyl-, and N-guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents

YesCurrent drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivatives with submicromolar potencies against T. brucei. Among these compounds, the guanidinononyltacrine analogue 15e exhibits a 5-fold increased antitrypanosomal potency, 10-fold increased selectivity, and 100-fold decreased anticholinesterasic activity relative to the parent huprine Y. Its biological profile, lower molecular weight relative to dimeric compounds, reduced lipophilicity, and ease of synthesis, make it an interesting anti-HAT lead, amenable to further optimization to eliminate its remaining anticholinesterasic activity.Wellcome Trus

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities