Behavioural effects of novel multitarget anticholinesterasic derivatives in Alzheimer’s disease Lydia Giménez-Llort a,b , Miriam Ratia a,c , Belén Pérez a,c , Pelayo Camps d,e , Diego Muñoz-Torrero d,e , Albert Badia a,c and M. Victoria Clos a,c The current pharmacological approach to Alzheimer’s disease (AD) treatment, mostly based on acetylcholinesterase inhibitors (AChEIs), is being revisited, especially in terms of the temporal frames and the potential benefits of their noncanonic actions, raising the question of whether inhibitors of AChE might also act in a disease- modifying manner. Besides, in the last decades, the pharmacophoric moieties of known AChEIs have been covalently linked to other pharmacophores in the pursuit of multitarget hybrid molecules that are expected to induce long-lasting amelioration of impaired neurotransmission and clinical symptoms but also to exert disease-modifying effects. Our research consortium has synthesized and defined the pharmacological profile of new AChEIs derivatives of potential interest for the treatment of AD. Among these, huprines and derivatives have been characterized successfully. Huprine X, a reversible AChE inhibitor, designed by molecular hybridization of tacrine and huperzine A, has been shown to affect the amyloidogenic process in vitro, and the AD-related neuropathology in vivo in mice models of the disease. More recently, we have shown that a group of donepezil–huprine heterodimers exerts a highly potent and selective inhibitory action on AChE both in vitro and ex vivo, simultaneously interacting with both peripheral and catalytic binding sites, and inhibiting the β-amyloid aggregation, whereas some levetiracetam–huprine hybrids have been shown to reduce epileptiform activity, neuroinflammation and amyloid burden in an animal model of AD. Here, we summarize the behavioural correlates of these noncanonic actions as assessed in three distinct biological scenarios: middle-age, cognitive deficits associated with ageing and AD-like phenotype in mice. Besides the improvement in the hallmark cognitive symptomatology without inducing side effects, these drugs have shown to be able to modulate emotional and anxiety-like behaviours or to reduce spontaneous seizures, all of them related to the so-called ‘behavioural and psychological symptoms of dementia’ . Overall, the studies show that these novel multitarget anticholinesterasics exert noncanonic actions providing symptomatic and disease-modifying benefits of potential interest for the management of AD. Behavioural Pharmacology 28:124–131 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Behavioural Pharmacology 2017, 28:124–131 Keywords: acetylcholinesterase inhibitors, animal models, behavioural and psychological symptoms of dementia, cognition, disease-modifying mechanisms, drug development, learning and memory, noncanonic actions, seizures a Institut de Neurociències, b Department of Psychiatry and Forensic Medicine, c Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, d Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences and e Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain Correspondence to Lydia Giménez-Llort, PhD, Department of Psychiatry and Forensic Medicine, Medical Psychology Unit, School of Medicine, Autonomous University of Barcelona, Avinguda Can Domènech, Edifici M, s/n, Campus Bellaterra, Cerdanyola del Vallès, 08193 Barcelona, Spain E-mail: lidia.gimenez@uab.cat Received 17 September 2016 Accepted as revised 4 January 2017 Classical cholinergic hypothesis, current anticholinesterase inhibitors and cognitive impairment in Alzheimer’s disease Since the postulation of the cholinergic hypothesis of age-related cognitive dysfunction by Bartus et al. (1982), it is well accepted that the cholinergic neurotransmission is one of the most important circuits involved in the cognitive function, with learning and memory standing out among the many higher brain functions under its control (Levey, 1996). Moreover, considerable experi- mental and neuropathological evidence points out severe loss of neurotransmission in the basal forebrain ascending cholinergic system not only as a major contributor of age- related cognitive impairment but also of Alzheimer’s disease (AD) cognitive symptoms (Bartus, 2000; Auld et al., 2002). Thus, among the hallmarks of the disease, the loss of synapses, mainly cholinergic, determines a significant cognitive decline, which leads to progressive loss of relevant higher functions. Memory, communica- tion skills (language and speech), visual-spatial orientation and executive functions characterize the clinical symp- toms of AD and the degree of global deterioration of the patient. Accordingly, ‘cognitive enhancement’ by means of the stimulation of central cholinergic neurotransmis- sion, considered a strategy to counteract age-related cog- nitive decline, also became a first-line symptomatic therapy for AD. Among all the compounds that can potentiate the choli- nergic neurotransmission in the central nervous system, 124 Review article 0955-8810 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/FBP.0000000000000292 Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved.