LPA₁ and LPA₂ receptors as new therapeutic targets for the treatment of central nervous system pathologies

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica, leída el 05-05-2017Los lisofosfolípidos son derivados lípidicos con funciones tanto estructurales como de señalización, por lo que juegan un papel fundamental en humanos y otros mamíferos. El análisis de lisofosfolípidos en fluidos humanos de pacientes con diferentes condiciones patológicas revela no sólo la importancia de los lisofosfolípidos y de sus receptores en enfermedades humanas, sino también sus potenciales aplicaciones como biomarcadores y/o dianas terapéuticas.1,2 Entre ellos, destaca el ácido lisofosfatídico (LPA) debido a su implicación en la regulación de procesos fisiológicos y patológicos de importancia a través de la activación de sus receptores correspondientes LPA1–6,3-5 todos ellos pertenecientes a la superfamilia de los receptores acoplados a proteínas G (GPCRs). El LPA regula una amplia variedad de actividades biológicas, especialmente en el desarrollo y el funcionamiento del sistema nervioso.6,7 Considerando los numerosos efectos producidos por el LPA en diferentes tipos celulares del sistema nervioso y la sobreexpresión de los receptores de LPA como consecuencia de un daño neuronal observado tanto en ratones como en humanos, es probable que el LPA regule aspectos esenciales en la reorganización celular después de un trauma neuronal.8 Entre todas las neuropatologías donde el LPA juega un papel importante, el dolor neuropático9-13 y el daño medular14-16 son condiciones con una elevada incidencia y altamente incapacitantes, que actualmente carecen de terapias específicas. En este contexto, los receptores LPA1 y LPA2 se han relacionado con estas patologías,17,18 pero la falta de agonistas y antagonistas potentes y selectivos ha dificultado el estudio de sus funciones específicas. Por tanto, en este trabajo, hemos abordado el desarrollo de ambos tipos de compuestos para así tratar de esclarecer la función de los receptores LPA1 y LPA2 en el dolor neuropático y en el daño medular...Lysophospholipids (LPs) are cell membrane lipid derivatives that also act as extracellular signals and play important roles in humans and other mammals. Analysis of LPs in human body fluids from subjects with different pathophysiological conditions reveal not only the relevance of LPs and their receptors in human diseases, but also their potential application as biomarkers and/or therapeutic targets.1,2 Among them, lysophosphatidic acid (LPA) stands out as a molecule that elicits a plethora of biological effects by binding to specific G protein-coupled receptors: LPA1–6 receptors.3-5 LPA regulates a wide variety of biological activities, notably within the developing and adult nervous system.6,7 Considering the pleiotropic effects of LPA on many nervous system cell types, together with data showing localized up-regulation of LPA receptors after injury in mice and humans, it is likely that LPA regulates essential aspects of the cellular reorganization after neural trauma.8 Among all neuropathologies where LPA plays an important role, neurophatic pain (NP)9-13 and spinal cord injury (SCI)14-16 are high incidence and seriously disabling conditions which currently lack specific pharmacological therapies. In this context, LPA1 and LPA2 receptor subtypes have been functionally linked to many neural processes associated to these pathologies,17,18 but the lack of potent and selective agonists and antagonists has impaired the delineation of their specific role. Hence, we have focused our efforts on the development of such agents to clarify the biological role of LPA1 and LPA2 receptors in NP and SCI...Depto. de Química OrgánicaFac. de Ciencias QuímicasTRUEunpu

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice

Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA2) has recently emerged as a new potential pharmacological approach to decrease SCIassociated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA2 antagonists, among which compound 54 (UCM14216) stands out as a potent and selective LPA2 receptor antagonist (Emax = 90%, IC50 = 1.9 μM, KD = 1.3 nM; inactive at LPA1,3−6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA2-dependent manner, confirming the potential of LPA2 inhibition for providing a new alternative for treating SCI

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The status of the lysophosphatidic acid receptor type 1 (LPA1R)

Lysophospholipids are lipid molecules that are receiving growing attention because, in addition to their structural function in the cell membrane, they are now regarded as important regulators for diverse biological functions through activation of specific receptors. These receptors have been characterized during the last two decades as G protein-coupled receptors (GPCRs) and, among them, two families stand out: lysophosphatidic acid (LPA1–6) and sphingosine 1-phoshate (S1P1–5) receptors. Despite their interest, the high structural similarity between them has restrained the development of selective and high affinity ligands and therefore the elucidation of the role of these receptors in the central nervous system (CNS). This review provides an overview about the different LPA receptors with a special focus on the LPA1 subtype from a medicinal chemistry perspective. It summarizes the most recent developments in the search for selective and specific agonists and antagonists of the LPA1 receptor and highlights their current status in the drug development pipeline

Iodine(III)-Mediated Intermolecular Allylic Amination under Metal-Free Conditions

A new approach to direct intermolecular allylic amination has been developed using metal-free conditions at room temperature. The reaction employs a hypervalent iodine­(III) reagent as an oxidant and bistosylimide as a nitrogen source. A series of different allylic aminations are presented with up to a 99% yield. Mechanistic studies including isotope labeling and Hammett correlation suggest that depending on the substrate structure two different mechanisms can be operating

Iodine(III)-Mediated Intermolecular Allylic Amination under Metal-Free Conditions

A new approach to direct intermolecular allylic amination has been developed using metal-free conditions at room temperature. The reaction employs a hypervalent iodine­(III) reagent as an oxidant and bistosylimide as a nitrogen source. A series of different allylic aminations are presented with up to a 99% yield. Mechanistic studies including isotope labeling and Hammett correlation suggest that depending on the substrate structure two different mechanisms can be operating

Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons

Cannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1 receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington's disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoid system in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-α in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8 mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGLfloxed/floxed;GFAP-Cre/+ mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration

A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration.

Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax = 118%, EC50 = 0.24 μM, KD = 19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP