Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

TRPM8 ion channels, the primary cold sensors in humans, are activated by innocuous cooling (<28 °C) and cooling compounds (menthol, icilin) and are implicated in sensing unpleasant cold stimuli as well as in mammalian thermoregulation. Overexpression of these thermoregulators in prostate cancer and in other life-threatening tumors, along with their contribution to an increasing number of pathological conditions, opens a plethora of medicinal chemistry opportunities to develop receptor modulators. This Perspective seeks to describe current known modulators for this ion channel because both agonists and antagonists may be useful for the treatment of most TRPM8-mediated pathologies. We primarily focus on SAR data for the different families of compounds and the pharmacological properties of the most promising ligands. Furthermore, we also address the knowledge about the channel structure, although still in its infancy, and the role of the TRPM8 protein signalplex to channel function and dysfunction. We finally outline the potential future prospects of the challenging TRPM8 drug discovery fieldWe thank Gregorio Fernández-Ballester for the figure of the TRPM8 homology model. Funding from the Ministry of Economy and Competitiveness (BFU 2012-39092-C02; SAF2015-66275-C2-R) and the Generalitat Valenciana (PROMETEO II/2014/011).Peer reviewe

1,1,3,3-tetramethylguanidinium dihydrogenorthophosphate

In the title compound, C 5 H 14 N 3 + H 2 PO 4 ˇ , the cation has a central guanidinium fragment with a planar geometry, as expected for a central C sp 2 atom with a small charge delocalization along the three C–N bonds. The crystal packing is governed by hydrogen bonds so that the phosphate anions are linked head to tail, forming chains running parallel to the c direction. These chains in turn are interconnected by hydrogen bonds to intermediate tetramethylguanidinium cations forming hydrogen-bonded molecular layers stacked parallel to the bc crystal planesCICYT PB98-112

Benzyltrimethylammonium dihydrogen orthophosphate monohydrate

The title compound, C 10 H 16 N + H 2 PO 4 H 2 O, crystallizes in the centrosymmetric space group P 2 1 / c with two independent molecules in the asymmetric unit. Therefore, nonlinear optical properties are absent. The crystal packing is governed by hydrogen bonds, so that the phosphate anions are linked head- to-tail, forming chains running parallel to the a direction. These chains in turn are interconnected by hydrogen bonds to water molecules, forming hydrogen-bonded molecular layers stacked parallel to the ab planeCICYT BFM2002-03327FEDE

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)

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

Helical peptides from VEGF and Vammin hotspots for modulating the VEGF-VEGFR interaction

The design, synthesis, conformational studies and binding affinity for VEGF receptors of a collection of linear and cyclic peptide analogues of the N-terminal α-helix fragments 13-25 of VEGF and 1-13 of Vammin are described. Linear 13(14)-mer peptides were designed with the help of an AGADIR algorithm and prepared following peptide solid-phase synthetic protocols. Cyclic peptide derivatives were prepared on-resin from linear precursors with conveniently located Glu and Lys residues, by the formation of amide linkages. Conformational analysis, CD and NMR, showed that most synthesized peptides have a clear tendency to be structured as α-helices in solution. Some of the peptides were able to bind a VEGFR-1 receptor with moderate affinity. In addition to the described key residues (Phe17, Tyr21 and Tyr25), Val14 and Val20 seem to be relevant for affinity.Peer Reviewe

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

Discovery of New Antagonists for TRPM8 Channel by High Throughput Assay

Trabajo presentado en el IV RECI: New Horizons in Ion Channel Research, celebrado en Cuenca (España) del 12 al 13 de febrero de 2013.TRP ion channels family is represented by 85 members that can be organized by their sequence homology into seven subfamilies. Some members of these subfamilies play an important role in detecting temperature changes. Within TRPV (vanilloid) subfamily, TRPV1 is the most studied member, and has been related with chronic pain, furthermore its pharmacological blockade and genetic deletion experiments have validated TRPV1 as a therapeutic target. Another member of the TRP family is TRPA1, which is activated by noxious cold and chemical compounds including allyl isothiocyanate (AITC), the pungent principle of wasabi and other mustard oils. TRPA1 appears to have a central role in the pain response but also it has been demonstrated that is essential for asthma [1]. TRP melastatin 8 (TRPM8) is activated by chemical cooling agents (such as menthol) or by temperatures between 28-15 ºC, mediating the detection of innocuous cold thermal stimuli. TRPM8 expression up-regulates has been suggested to play an important role in carcinogenesis and related with prostate cancer [2]. In this study was evaluated the biological activity of a new chemical library, through high throughput screening. We report here the identification of compounds presented a high blockade activity on TRPM8 and share common structure. These hits with notorious antagonistic effect were selected and observed in patch-clamp experiments performed in stable cell lines that expressed TRPV1, TRPM8 and TRPA1 to characterize more accurately their properties. These new pharmacophoric scaffolds can be used as a hit to develop new compounds with better modulator properties interesting to the clinical field or as a research tool.Supported by Consolider-Ingenio 2010 (CSD2008-00005), MICINN (BFU2009- 08346), MICCIN (BES-2010-037112), La Fundacion La Marato de TV3, PrometeoGVA and SAF2009-09323Peer reviewe

A Milky Way-like barred spiral galaxy at a redshift of 3

International audienceThe majority of massive disk galaxies in the local Universe show a stellar barred structure in their central regions, including our Milky Way. Bars are supposed to develop in dynamically cold stellar disks at low redshift, as the strong gas turbulence typical of disk galaxies at high redshift suppresses or delays bar formation. Moreover, simulations predict bars to be almost absent beyond $z = 1.5$ in the progenitors of Milky Way-like galaxies. Here we report observations of ceers-2112, a barred spiral galaxy at redshift $z_{\rm phot} \sim 3$, which was already mature when the Universe was only 2 Gyr old. The stellar mass ($M_{\star} = 3.9 \times 10^9 M_{\odot}$) and barred morphology mean that ceers-2112 can be considered a progenitor of the Milky Way, in terms of both structure and mass-assembly history in the first 2 Gyr of the Universe, and was the closest in mass in the first 4 Gyr. We infer that baryons in galaxies could have already dominated over dark matter at $z \sim 3$, that high-redshift bars could form in approximately 400 Myr and that dynamically cold stellar disks could have been in place by redshift $z = 4-5$ (more than 12 Gyrs ago)

Mutational screening of newly diagnosed multiple myeloma patients by deep targeted sequencing

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