Elongation of the Hydrophobic Chain as a Molecular Switch:Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists

The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca2+ permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions.We gratefully acknowledge financial support from Universitat de Lleida, Ministerio de Educación, Cultura y Deporte and Banco Santander (Programa UdL-Impuls). The authors are grateful to the Serveis Cientifictècnics (SCT) of the Universitat de Lleida for providing us with spectroscopic and chromatographic facilities. We acknowledge Dr. Alberto Minassi, Dipartimento di Scienze del Farmaco, Universitàdel Piemonte Orientale, Novara, Italy, for the kind gift of olvanil

New contributions to the preparation of compounds derived from L-cysteine with biological activity

Una gran varietat de productes naturals i fàrmacs que inclouen sofre en les seves estructures presenten diverses activitats biològiques i aplicacions. Un exemple és la L-cisteïna, un aminoàcid essencial necessari en processos bioquímics dels éssers vius. D’una banda, aquest treball es centra en l’obtenció de tiazolidines a partir de la L-cisteïna amb un grau de qualitat alimentària. La metodologia es basa en un procés de síntesi en continu i en un sistema d’assecatge d’atomització. A més, es va realitzar un estudi per investigar el rol de la tiazolidina derivada de la D-ribosa com a agent quimioprotector i modulador de glutatió en un model AOM/DSS de carcinogènesi en ratolins. Addicionalment, es van modificar les tiazolidines per tal d'augmentar les seves propietats lipòfiles en vista al seu ús com additius alimentaris en una àmplia varietat de matrius d'aliments. D’altra banda, es van sintetitzar compostos tipus capsaicinoid que incorporaven L-cisteïna i anàlogs en la seva estructura i es avaluar la seva activitat en el receptor TRPV1, que exerceix un paper important com a nexe en la transmissió del dolor. La síntesi, la relació estructura-activitat i els resultats biològics es descriuen en aquest document.Una gran variedad de productos naturales y fármacos que incluyen azufre en sus estructuras presentan diversas actividades biológicas y aplicaciones. Un ejemplo es la L-cisteína, un aminoácido esencial requerido en ciertos procesos bioquímicos de los seres vivo. De una banda, este trabajo se centra en la obtención de tiazolidinas a partir de L-cisteína con grado de calidad alimentaria. La metodología se basa en un proceso de síntesis en continuo y en un sistema de secado por polvorización. También se realizó un estudio para investigar el efecto de la tiazolidina derivada de la D-ribosa como agente quimioprotector y modulador del glutatión en un modelo AOM/DSS de carcinogénesis en ratones i. Adicionalmente, se modificaron las tiazolidines para aumentar sus propiedades lipófilas con objectivo de su uso com aditivos alimentarios en una amplia variedad de matrices alimentarias. Por otra parte, se sintetizaron compuestos tipo capsaicinoide que incorporavan L-cisteína y análogos en su estructura y se evaluó su actividad en el receptor TRPV1, que ejerce un papel importante como a nexo en la transmisión del dolor. La síntesis, la relación estructura-actividad y los resultados biológicos se describen en este documento.A wide variety of sulphur-containing compounds that exist in natural products and drugs present different biological activities and applications. One example is the L-cysteine, an amino acid required for essential biochemical processes in living organisms. On the one hand, this work focuses on the production of thiazolidine-4(R)-carboxylates derived from L-cysteine with food grade quality. The methodology was based on combining a continuous flow reaction and a spray-drying system. Additionally, an study was performed to investigate the role of thiazolidine derived from D-ribose as chemoprotector agent and modulator of glutathione status in a mouse model of AOM/DSS-induced carcinogenesis. Moreover, the highly soluble thiazolidines-4(R)-carboxylic acid derivatives were modified to increase their lipophilicity wih interests to use these thiazolidine derivatives as food ingredients in a wide variety of food matrices. On the other hand, it has been synthesized new capsaicinoid-like compounds incorporating L-cysteine and analogues and it was evaluated their activity on TRPV1, which plays an important role as a nexus in pain transmission. Their synthesis, the structure-activity relationships and biological results are presented

Elongation of the Hydrophobic Chain as a Molecular Switch:Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists

The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca2+ permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions