Role of the transient receptor potential vanilloid 1 in inflammation and sepsis

The transient receptor potential vanilloid 1 (TRPV1) is a thermoreceptor that responds to noxious temperatures, as well as to chemical agonists, such as vanilloids and protons. In addition, its channel activity is notably potentiated by proinflammatory mediators released upon tissue damage. The TRPV1 contribution to sensory neuron sensitization by proalgesic agents has signaled this receptor as a prime target for analgesic and anti-inflammatory drug intervention. However, TRPV1 antagonists have notably failed in clinical and preclinical studies because of their unwanted side effects. Recent reports have unveiled previously unrecognized anti-inflammatory and protective functions of TRPV1 in several diseases. For instance, this channel has been suggested to play an anti-inflammatory role in sepsis. Therefore, the use of potent TRPV1 antagonists as a general strategy to treat inflammation must be cautiously considered, given the deleterious effects that may arise from inhibiting the population of channels that have a protective function. The use of TRPV1 antagonists may be limited to treating those pathologies where enhanced receptor activity contributes to the inflamed state. Alternatively, therapeutic paradigms, such as reduction of inflammatory-mediated increase of receptor expression in the cell surface, may be a better strategy to prevent abrogation of the TRPV1 subpopulation involved in anti-inflammatory and protective processes

1,3-diphenylpropan-1-ones as allosteric modulators of α7 nACh receptors with analgesic and antioxidant properties

Nicotine acethylcholine receptors (nAChRs) play critical roles in cognitive processes, neuroprotection and inflammation. Results: According to their substituents, 1,3-diphenylpropan-1-one derivatives act as α7 nAChRs negative allosteric modulators (NAM, OMe) or Type I positive allosteric modulators (PAMs, OH). Compounds 7 and 31 were the most effective (989 and 666% enhancement of ACh-induced currents) and potent (EC: 12.9 and 6.85 μM) PAMs. They exhibited strong radical scavenging values. Compound 31, selective over other neuronal nAChR subtypes and with acceptable pharmacokinetic profile, showed antinociceptive effects in a model of inflammatory pain. Conclusion: Compound 31 is a novel, potent and selective α7 nAChR PAM, displaying antioxidant and analgesic activities. The 1,3-diphenylpropan-1-one scaffold could be the base toward more advanced type I PAMs for the treatment of nAChR-mediated diseases.This work was supported by the Spanish MINECO: CSD2008-00005, The Spanish Ion Channel Initiative-CONSOLIDER INGENIO 2010, SAF2011-22802 and BFU2012-39092-C02. The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”. We thank Susana Cámara Garrido for her assistance in the synthesis of some starting compounds and Susana Gerber for technical assistance. BBP thanks the CSIC for a predoctoral fellowship (JAE-Predoc from Junta para la Ampliación de Estudios, co-financed by FSE). Alpha7 nAChRPeer Reviewe

The TRPM8 antagonist RGM8-51 displays analgesic activity in different pain models

TRPM8 channels are overexpressed in sensory neurons after nerve injury or inflammation, resulting in enhanced sensitivity (allodynia and hyperalgesia) to physical stimulation, and have been implicated in migraine, but the interest of TRPM8 antagonists is still a matter of controversy (1,2). The aim of our work was to evaluate the analgesic activity of a TRPM8 antagonist, RGM8-51, in different pain models, looking for similarities and differences with other antagonists. To this end, we used the mouse oxaliplatin-induced peripheral neuropathy, the chronic constriction injury of the rat sciatic nerve (CCI) and mouse NTG-induced migraine-like models. Compound RGM8- 51 reduces the cold allodynia induced by oxaliplatin, from 15 to 60 min after administration (0.1-1 μg, i.pl.), decreases the nocifensive responses to cold, heat and mechanical stimuli in the CCI model (10 μg, i.pl., 30 mg/Kg, i.p.), and relief chronic pain associated to migraine in mouse, in a sex-dependent manner (10 or 30 mg/Kg, i.v.). The β–lactam derivative RGM8-51 not only has analgesic activity in all assayed animal models, but also seems to have a different mode of interaction with the TRPM8 channel than other antagonists, as suggested by docking studies

Generation of Molecular Diversity from Amino Acids. A Source for the Discovery of New TRP Channel Modulators

Trabajo presentado en el IV RECI: New Horizons in Ion Channel Research, celebrado en Cuenca (España) del 12 al 13 de febrero de 2013.Ion channels are central and challenging targets in medicinal chemistry but, because of the scarce structural knowledge, rational approaches to ion channel modulators are still rare. Moreover, the multimodal activation of some channels, like TRPs, complicates still more the scenario for rational discovery programs. Due to these facts, most strategies directed to identify ion channel modulators rely on the screening of peptide and small-molecule libraries. In this context, we have been involved in the development of synthetic pathways for the generation of diverse, chiral, highly functionalized linear and heterocyclic scaffolds from amino acids, and in the production of discrete libraries from them. The screening of these libraries on different TRP channels has allowed the discovery of some innovative hits that have progressed to hit-to-lead optimization programs. This communication will deal with the synthesis, structural characterization, and biological evaluation of a collection of β,γ–diaminoester derivatives that display significant activity at TRPV1, TRPM8 and TRPA1 channels. Compound RGM04-7, a selective.Supported by MICINN grants: Consolider-Ingenio 2010 (CSD2008-00005 and CSD2006-00015), SAF2009-09323 and BFU2009-08346, and the Generalitat Valenciana (PROMETEO/2010/046)

The Relationship between Information Utilization and Social Participation among Middle-aged and Older Adults

早大学位記番号:新8355早稲田大

Péptidos bloqueantes de termoreceptores y sus usos

La invención se relaciona con péptidos helicoidales capaces de modular la activación de canales termosensoriales y con sus aplicaciones. Más concretamente, la invención se relaciona con péptidos con capacidad de bloquear la activación de los canales TRPV1 y TRPVA por parte de sus ligandos, con composiciones farmacéuticas que comprenden dichos péptidos y con el uso de dichos péptidos y dichas composiciones farmacéuticas para el tratamiento de dolor, inflamación, prurito, enfermedades de las vías respiratorias, enfermedades de la piel, mucosa y/o uñas y desórdenes asociados con desequilibrios del calcio.Peer reviewedUniversidad Miguel Hernández de Elche, Consejo Superior de Investigaciones CientíficasR Informe sobre el estado de la técnica publicado separadament

β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models

Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases

DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target

15 pags, 8 figs, 3 tabs. -- Supplementary data to this article can be found online at https://doi.org/10.1016/j.bioorg.2021.105231.The analgesic peptide DD04107 (Pal-EEMQRR-NH2) and its acetylated analogue inhibit α-calcitonin gene-related peptide (α-CGRP) exocytotic release from primary sensory neurons. Examining the crystal structure of the SNARE-Synaptotagmin-1(Syt1) complex, we hypothesized that these peptides could inhibit neuronal exocytosis by binding to Syt1, hampering at least partially its interaction with the SNARE complex. To address this hypothesis, we first interrogate the role of individual side-chains on the inhibition of α-CGRP release, finding that E1, M3, Q4 and R6 residues were crucial for activity. CD and NMR conformational analysis showed that linear peptides have tendency to adopt α-helical conformations, but the results with cyclic analogues indicated that this secondary structure is not needed for activity. Isothermal titration calorimetry (ITC) measurements demonstrate a direct interaction of some of these peptides with Syt1-C2B domain, but not with Syt7-C2B region, indicating selectivity. As expected for a compound able to inhibit α-CGRP release, cyclic peptide derivative Pal-E-cyclo[EMQK]R-NH2 showed potent in vivo analgesic activity, in a model of inflammatory pain. Molecular dynamics simulations provided a model consistent with KD values for the interaction of peptides with Syt1-C2B domain, and with their biological activity. Altogether, these results identify Syt1 as a potential new analgesic target.This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO-FEDER), RTI2018-097189-C2 and CTQ2017-84371-P), and the Spanish National Research Council (CSIC, 201880E109, 201980E030). The NMR experiments were performed in the “Manuel Rico” NMR laboratory, LMR, CSIC, a node of the Spanish Large-Scale National Facility ICTS R-LRB. We thank Prof. Josep Rizo and R. Voleti (Dept. Biophysics, Biochemistry and Pharmacology, UT Southwestern Medical Center, Dallas, USA) for providing the clones required for expressing Syt1 and Syt7 proteins. SG-R and AB belong to the Instituto de Investigación Sanitaria del Principado de Asturias (ISPA).Peer reviewe

Composición farmaceútica para el tratamiento de la epifora

La invención se relaciona con composiciones terapéuticas para el tratamiento de la epífora y, más concretamente con composiciones que comprenden un antagonista del receptor TRPM8.Peer reviewedUniversidad Miguel Hernández de Elche, Consejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Progress in the Structural Basis of thermoTRP Channel Polymodal Gating

The thermosensory transient receptor potential (thermoTRP) family of ion channels is constituted by several nonselective cation channels that are activated by physical and chemical stimuli functioning as paradigmatic polymodal receptors. Gating of these ion channels is achieved through changes in temperature, osmolarity, voltage, pH, pressure, and by natural or synthetic chemical compounds that directly bind to these proteins to regulate their activity. Given that thermoTRP channels integrate diverse physical and chemical stimuli, a thorough understanding of the molecular mechanisms underlying polymodal gating has been pursued, including the interplay between stimuli and differences between family members. Despite its complexity, recent advances in cryo-electron microscopy techniques are facilitating this endeavor by providing high-resolution structures of these channels in different conformational states induced by ligand binding or temperature that, along with structure-function and molecular dynamics, are starting to shed light on the underlying allosteric gating mechanisms. Because dysfunctional thermoTRP channels play a pivotal role in human diseases such as chronic pain, unveiling the intricacies of allosteric channel gating should facilitate the development of novel drug-based resolving therapies for these disorders