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

Derivados de 1,3-dioxoperhidropirido[1,2-c]pirimidinas como antagonistas de colecistoquinina

Referencia OEPM: P9501857.-- Fecha de solicitud: 26/09/1995.-- Titulares: Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Navarra.Derivados de 1,3-dioxoperhidropirido[1,2-c]pirimidinas como antagonistas de colecistoquinina (ver figura en archivo de texto adjunto). La presente invención se refiere a derivados de 1,3- dioxoperhidropirido [1,2,-c] piriminas, e intermedios para su preparación de fórmula general (I). Dichos derivados son útiles como antagonistas de colecistoquinina (CCK) y por lo tanto como agentes activos sobre el sistema nervioso central y el periférico.Peer reviewe

Trpm8 channels: Advances in structural studies and pharmacological modulation

The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by volt-age, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which in-clude urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.The research group was funded by the Spanish Ministerio de Ciencia y Universidades (MICYU-FEDER, RTI2018-097189-C2-2 to R.G.-M. and M.M.-M.) and the Spanish National Research Council (CSIC, 201880E109 to M.M.-M. and 201980E030 to R.G.-

Recent Progress in TRPM8 Modulation: An Update

The transient receptor potential melastatin subtype 8 (TRPM8) is a nonselective, multimodal ion channel, activated by low temperatures (&lt;28 &#176;C), pressure, and cooling compounds (menthol, icilin). Experimental evidences indicated a role of TRPM8 in cold thermal transduction, different life-threatening tumors, and other pathologies, including migraine, urinary tract dysfunction, dry eye disease, and obesity. Hence, the modulation of the TRPM8 channel could be essential in order to understand its implications in these pathologies and for therapeutic intervention. This short review will cover recent progress on the TRPM8 agonists and antagonists, describing newly reported chemotypes, and their application in the pharmacological characterization of TRPM8 in health and disease. The recently described structures of the TRPM8 channel alone or complexed with known agonists and PIP2 are also discussed

Studies on N-deprotection of ψ(CH2NH) pseudodipeptide methyl esters. Cyclization to 2-ketopiperazines

N-Deprotection of Z- and Boc-aminomethylene pseudodipeptide methyl esters yielded not only the expected linear deprotected compounds but also the 2-ketopiperazine cyclic analogues. The extent of lactamization was found to be dependent on the nature of the amino acid, the sequence order, and the deprotection conditions. Hydrogenation of Z-pseudodipeptides containing N-terminal basic amino acids in acidic media afforded linear compounds, while replacement of these basic residues by Leu gave mixtures of linear and cyclic pseudodipeptides. The reverse-sequence analogues, with Lys or Arg at the C-terminus, yielded the corresponding 2-ketopiperazines as the only reaction products. Opposite results were obtained for C-terminal Leu derivatives in which almost no cyclization occurred. Hydrogenation under neutral conditions gave mainly cyclic derivatives, while linear analogues were predominant after treatment of Boc-protected pseudodipeptides with trifluoroacetic acid or HCl.This work was supported by the Comision Interministerial de Ciencia y Tecnologia (FAR 88-0298).

Stereospecific synthesis of (2R,3S)-3-amino-2-piperidineacetic acid derivatives for use as conformational constraint in peptides

Catalytic hydrogenation at 40°C of the β-ketoester, obtained from Boc-Orn (Z)-OH and ethyl lithioacetate, provides exclusively ethyl (2R,3S)-3-tert-butyloxycarbonylamino-2-piperidineacetic acid which when suitably protected, can be used for peptide synthesis

On the modulation of TRPM channels: Current perspectives and anticancer therapeutic implications

The transient melastatin receptor potential (TRPM) ion channel subfamily functions as cellular sensors and transducers of critical biological signal pathways by regulating ion homeostasis. Some members of TRPM have been cloned from cancerous tissues, and their abnormal expressions in various solid malignancies have been correlated with cancer cell growth, survival, or death. Recent evidence also highlights the mechanisms underlying the role of TRPMs in tumor epithelial-mesenchymal transition (EMT), autophagy, and cancer metabolic reprogramming. These implications support TRPM channels as potential molecular targets and their modulation as an innovative therapeutic approach against cancer. Here, we discuss the general characteristics of the different TRPMs, focusing on current knowledge about the connection between TRPM channels and critical features of cancer. We also cover TRPM modulators used as pharmaceutical tools in biological trials and an indication of the only clinical trial with a TRPM modulator about cancer. To conclude, the authors describe the prospects for TRPM channels in oncology

Synthesis of 8-amino-3-oxoindolizidine-1-carboxylic acid derivatives as conformationally restricted templates for use in design of peptide mimetics

The synthesis of new 8-tert-bytyloxycarbonylamino-3-oxoindolizidine-1-carboxylic acid esters with different stereochemistry at position 1, 8, and 8a is described. Three different paths from ornithine derivatives have been utilized. These compounds can be employed as new templates in synthetic analogues of bioactive peptides. Starting from ornithine derivatives, three different synthetic methods for the preparation of the title compounds with different stereochemistry at positions 1, 8, and 8a are described.We thank the Comisión Interministerial de Ciencia y Tecnología (FAR 91-1120-C02-01) and Comunidad Autónoma de Madrid (C 167/91) for finantial support

Synthesis of methyl 6-aralkyl-2,5-diketopiperidine-3-carboxylates as synthons of conformationally constrained pseudopeptides

Catalytic hydrogenation of the 4-ketoesters 1a,b or 2a,b and their 5R-enantiomers, obtained from the corresponding Z-L- and Z-D-amino acid halomethyl ketones, directly leads to the methyl 6-aralkyl-2,5-diketopiperidine-3-carboxylates 3a,b and 4a,b and their 6R-enantiomers with high or moderate stereoselectivity at C-3

A facile synthesis of 8-amino-3-oxoindolizidine derivatives as conformationally restricted ornithyl pseudodipeptides

One pot procedure for the synthesis of 8-amino-3-oxoindolizidines from Zδ-protected ornithyl ketomethylene pseudodipeptide derivatives is described. This procedure, involving hydrogenolysis of the Z-group, intramolecular reductive amination and γ-lactamization, provides readily access to a variety of 3-oxoindolizidines of defined stereochemistry at C-8 and C-8a