Bioisosterism and conformational restriction: ligand-based design in the development of nicotinic ligands and melatonin analogues with neurogenic properties

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Química Farmacéutica, leída el 15-09-2014Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEunpu

Compuestos neurogénicos basados en melatonina y su uso en el tratamiento de enfermedades del sistema nervioso

La presente invención, que se incluye en el campo de la investigación e industria farmacéutica, se refiere a nuevas entidades químicas derivadas de melatonina con propiedades neurogénicas, moduladoras de los receptores de melatonina y/o serotonina, antioxidantes y/o colinérgicas. También se refiere a los procedimientos para la preparación de estos nuevos compuestos, a las composiciones farmacéuticas que los contienen y a su uso para la fabricación de un medicamento para el tratamiento de enfermedades del sistema nervioso relacionadas con degeneración neuronal, depresión, trastornos psiquiátricos y cognitivos, trauma o lesión celular, u otro trastorno neurológico relacionado, tratamiento de fatiga diurna, trastornos del sueño, pérdida de eficacia mental, debilidad e irritabilidad y síntomas relacionados con la descompensación horaria (efecto jet-lag o síndrome transoceánico).Peer reviewedConsejo Superior de Investigaciones Científicas, Universidad Autónoma de MadridB1 Patente sin examen previ

Assessing the Psychedelic "After-Glow" in Ayahuasca Users : Post-Acute Neurometabolic and Functional Connectivity Changes Are Associated with Enhanced Mindfulness Capacities

Ayahuasca is a plant tea containing the psychedelic 5-HT agonist N,N -dimethyltryptamine and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network, purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here, we investigated in an open-label uncontrolled study in 16 healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications and their association with mindfulness measures. Using 1 H-magnetic resonance spectroscopy and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior and anterior cingulate cortex after a single ayahuasca dose. Magnetic resonance spectroscopy showed post-acute reductions in glutamate+glutamine, creatine, and N-acetylaspartate+N-acetylaspartylglutamate in the posterior cingulate cortex. Connectivity was increased between the posterior cingulate cortex and the anterior cingulate cortex, and between the anterior cingulate cortex and limbic structures in the right medial temporal lobe. Glutamate+glutamine reductions correlated with increases in the "nonjudging" subscale of the Five Facets Mindfulness Questionnaire. Increased anterior cingulate cortex-medial temporal lobe connectivity correlated with increased scores on the self-compassion questionnaire. Post-acute neural changes predicted sustained elevations in nonjudging 2 months later. These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the posterior cingulate cortex, a key region within the default mode network, and increased connectivity between the anterior cingulate cortex and medial temporal lobe structures involved in emotion and memory potentially underlie the post-acute psychological effects of ayahuasca

The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro

Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.This work was supported by the MINECO (Grants SAF2010-16365 and SAF2014-52940-R to A.P-C and grants SAF2012-31035 and SAF2015-64948-C2-1-R to M.I.R.-F.), and was partially financed with FEDER funds. J.R. received funding from the Beckley Foundation. CIBERNED is funded by the Instituto de Salud Carlos III. J.A.M-G. is a post-doctoral fellow from CIBERNEDPeer Reviewe

Compuestos neurogénicos basados en melatonina y su uso en el tratamiento de enfermedades del sistema nervioso

La presente invención, que se incluye en el campo de la investigación e industria farmacéutica, se refiere a nuevas entidades químicas derivadas de melatonina con propiedades neurogénicas, moduladoras de los receptores de melatonina y/o serotonina, antioxidantes y/o colinérgicas. También se refiere a los procedimientos para la preparación de estos nuevos compuestos, a las composiciones farmacéuticas que los contienen y a su uso para la fabricación de un medicamento para el tratamiento de enfermedades del sistema nervioso relacionadas con degeneración neuronal, depresión, trastornos psiquiátricos y cognitivos, trauma o lesión celular, u otro trastorno neurológico relacionado, tratamiento de fatiga diurna, trastornos del sueño, pérdida de eficacia mental, debilidad e irritabilidad y síntomas relacionados con la descompensación horaria (efecto jet-lag o síndrome transoceánico).Peer reviewedConsejo Superior de Investigaciones Científicas, Universidad Autónoma de MadridA1 Solicitud de patente con informe sobre el estado de la técnic

Recent Advances in Neurogenic Small Molecules as Innovative Treatments for Neurodegenerative Diseases

The central nervous system of adult mammals has long been considered as a complex static structure unable to undergo any regenerative process to refurbish its dead nodes. This dogma was challenged by Altman in the 1960s and neuron self-renewal has been demonstrated ever since in many species, including humans. Aging, neurodegenerative, and some mental diseases are associated with an exponential decrease in brain neurogenesis. Therefore, the controlled pharmacological stimulation of the endogenous neural stem cells (NSCs) niches might counteract the neuronal loss in Alzheimer’s disease (AD) and other pathologies, opening an exciting new therapeutic avenue. In the last years, druggable molecular targets and signalling pathways involved in neurogenic processes have been identified, and as a consequence, different drug types have been developed and tested in neuronal plasticity. This review focuses on recent advances in neurogenic agents acting at serotonin and/or melatonin systems, Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase (NAMPT) and nuclear erythroid 2-related factor (Nrf2)

Neurogenic potential assessment and pharmacological characterization of 6-Methoxy-1,2,3,4-tetrahydro-β-carboline (Pinoline) and Melatonin-Pinoline Hybrids

This work received the honour of being the Cover of the ACS Chemical Neuroscience in its issue of May 20156-Methoxy-1,2,3,4-tetrahydro-β-carboline (pinoline) and N-acetyl-5-methoxytryptamine (melatonin) are both structurally related to 5-hydroxytryptamine (serotonin). Here we describe the design, synthesis, and characterization of a series of melatonin rigid analogues resulting from the hybridization of both pinoline and melatonin structures. The pharmacological evaluation of melatonin-pinoline hybrids comprises serotonergic and melatonergic receptors, metabolic enzymes (monoamine oxidases), antioxidant potential, the in vitro blood-brain barrier permeability, and neurogenic studies. Pinoline at trace concentrations and 2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (2) were able to stimulate early neurogenesis and neuronal maturation in an in vitro model of neural stem cells isolated from the adult rat subventricular zone. Such effects are presumably mediated via serotonergic and melatonergic stimulation, respectively.This work was supported by the Spanish Ministry of Economy and Competitiveness (Project SAF2012-31035), the Fundación de Investigacion Mediica Mutua Madrileña Automovilistica (AP103952012), and the CSIC (PIE-201280E074). M.F.R. had a JAE-Predoctoral Contract (Grant JAE-Pre-2009-106) from the Program “Junta para la Ampliación de Estudios” cofinanced by the CSIC and the European Social Fund.Peer Reviewe

Synthesis, pharmacological assessment, and molecular modeling of 6-chloro-pyridonepezils: New dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease

6-Chloro-pyridonepezils are chloropyridineedonepezil hybrids designed by combining the N-benzylpiperidine moiety present in donepezil with the 2-chloropyridine-3,5-dicarbonitrile heterocyclic ring system, both connected by an appropriate polymethylene linker. 6-Chloro-pyridonepezils 1-8 were prepared by reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2,6-dichloropyridine-3,5-dicarbonitrile (14)] with suitable 2-(1- benzylpiperidin-4-yl)alkylamines (9-12). The biological evaluation showed that these new compounds are cholinesterase inhibitors, in the submicromolar range, one of them (6) being a potent hBuChE inhibitor (IC50 = 0.47 ± 0.08 μM). 6-Chloro-pyridonepezils 4, 7 and 8 are potent hAChE inhibitors showing IC50 in the 0.013-0.054 μM range. Particularly, 6-chloro-pyridonepezil 8 is 625-fold more selective for hAChE than for hBuChE and compared to donepezil is equipotent for the inhibition of hAChE. Molecular modeling investigation on 6-chloro-pyridonepezils 4, 6-8 supports its dual AChE inhibitory profile, by binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The in vitro Blood Brain Barrier (BBB) and theoretical ADME analysis of 6-chloro-pyridonepezils 1-8 have been carried out. Overall, compound 8, is a permeable potent and selective dual AChEI that can be considered as a good candidate with potential impact for further pharmacological development in Alzheimer's therapy.Peer Reviewe