RESUMO
The first detailed phytochemical analysis of the cannabigerol (CBG)-rich chemotype IV of Cannabis sativa L. resulted in the isolation of the expected cannabigerolic acid/cannabigerol (CBGA/CBG) and cannabidiolic acid/cannabidiol (CBDA/CBD) and of nine new phytocannabinoids (5-13), which were fully characterized by HR-ESIMS and 1D and 2D NMR. These included mono- or dihydroxylated CBGA/CBG analogues, a congener with a truncated side chain (10), cyclocannabigerol B (11), and the CBD derivatives named cannabifuranols (12 and 13). Cyclocannabigerol B and cannabifuranols are characterized by a novel phytocannabinoid structural architecture. The isolated phytocannabinoids were assayed on the receptor channels TRPA1 and TRPM8, unveiling a potent dual TRPA1 agonist/TRPM8 antagonist profile for compounds 6, 7, and 14. Chiral separation of the two enantiomers of 5 resulted in the discovery of a synergistic effect of the two enantiomers on TRPA1.
Assuntos
Canabinoides , Cannabis , Canal de Cátion TRPA1 , Canais de Cátion TRPM , Canais de Potencial de Receptor Transitório , Cannabis/química , Canal de Cátion TRPA1/antagonistas & inibidores , Canabinoides/farmacologia , Canabinoides/química , Canabinoides/isolamento & purificação , Canais de Cátion TRPM/antagonistas & inibidores , Estrutura Molecular , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/química , Humanos , Canabidiol/farmacologia , Canabidiol/química , Canais de Cálcio/metabolismoRESUMO
Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one Δ(9)-tetrahydrocannabinol, and 2) the adaptive pro-homeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.
Assuntos
Canabinoides/farmacologia , Cannabis , Endocanabinoides/metabolismo , Receptores de Canabinoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Transdução de Sinais/fisiologiaRESUMO
α-Lipoic acid is a sulfur-containing nutrient endowed with pleiotropic actions and a safe biological profile selected to replace the unsaturated alkyl acid of capsaicin with the aim of obtaining lipoic amides potentially active as a TRPV1 ligand and with significant antioxidant properties. Thus, nine compounds were obtained in good yields following a simple synthetic procedure and tested for their functional TRPV1 activity and radical-scavenger activity. The safe biological profile together with the protective effect against hypoxia damage as well as the in vitro antioxidant properties were also evaluated. Although less potent than capsaicin, almost all lipoic amides were found to be TRPV1 agonists and, specifically, compound 4, the lipoic analogue of capsaicin, proved to be the best ligand in terms of efficacy and potency. EPR experiments and in vitro biological assays suggested the potential protective role against oxidative stress of the tested compounds and their safe biological profile. Compounds 4, 5 and 9 significantly ameliorated the mitochondrial membrane potential caused by hypoxia condition and decreased F2-isoprostanes, known markers of oxidative stress. Thus, the experimental results encourage further investigation of the therapeutic potential of these lipoic amides.
Assuntos
Capsaicina , Canais de Cátion TRPV , Humanos , Canais de Cátion TRPV/metabolismo , Antioxidantes/farmacologia , Amidas/farmacologia , Ligantes , Estresse Oxidativo , HipóxiaRESUMO
Focusing on the importance of the free phenolic hydroxyl moiety, a family of 23 alkylresorcinol-based compounds were developed and evaluated for their cannabinoid receptor binding properties. The non-symmetrical hexylresorcinol derivative 29 turned out to be a CB2-selective competitive antagonist/inverse agonist endowed with good potency. Both the olivetol- and 5-(2-methyloctan-2-yl)resorcinol-based derivatives 23 and 24 exhibited a significant antinociceptive activity. Interestingly, compound 24 proved to be able to activate both cannabinoid and TRPV1 receptors. Even if cannabinoid receptor subtype selectivity remained a goal only partially achieved, results confirm the validity of the alkylresorcinol nucleus as skeleton for the identification of potent cannabinoid receptor modulators.
Assuntos
Amidas/farmacologia , Analgésicos/farmacologia , Receptores de Canabinoides/metabolismo , Resorcinóis/farmacologia , Amidas/síntese química , Amidas/química , Analgésicos/síntese química , Analgésicos/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Estrutura Molecular , Ratos , Resorcinóis/química , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
As part of a study on triterpenoid conjugates, the dietary pentacyclic triterpenoids oleanolic (2a) and ursolic acids (3a) were coupled with vanillamine, and the resulting amides (2b and 3b, respectively) were assayed for activity on the vanilloid receptor TRPV1. Despite a structural difference limited to the location of a methyl group in their conformationally rigid pentacyclic core, oleanoloyl vanillamide dramatically outperformed ursoloyl vanillamide in terms of potency (EC50 = 35 ± 2 nM for 2b and 5.4 ± 2.3 µM for 3b). Using molecular docking and dynamics, this difference was translated into distinct accommodation modes at the TRPV1 vanillyl ligand pocket, suggesting a critical role of a C-H πphenyl interaction between the triterpenoid C-29 methyl and Phe591 of TRPV1. Because the molecular mechanisms underlying the activation process of transient receptor channels (TRPs) remain to be fully elucidated, the observation of spatially restricted structure-activity information is of significant relevance to identify the molecular detail of TRPV1 ligand gating.
Assuntos
Amidas/química , Descoberta de Drogas , Canais de Cátion TRPV/efeitos dos fármacos , Triterpenos/farmacologia , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Triterpenos/químicaRESUMO
Cannabitwinol (CBDD, 3), the second member of a new class of dimeric phytocannabinoids in which two units are connected by a methylene bridge, was isolated from a hemp (Cannabis sativa L.) industrial extract. The structural characterization of cannabitwinol, complicated by broadening of 1H NMR signals and lack of expected 2D NMR correlations at room temperature, was fully carried out in methanol-d4 at -30 °C. All the attempts to prepare CBDD by reaction of CBD with formaldehyde or its iminium analogue (Eschenmoser salt) failed, suggesting that this sterically congested dimer is the result of enzymatic reactions on the corresponding monomeric acids. Analysis of the cannabitwinol profile of transient receptor potential (TRP) modulation evidenced the impact of dimerization, revealing a selectivity for channels activated by a decrease of temperature (TRPM8 and TRPA1) and the lack of significant affinity for those activated by an increase of temperature (e.g., TRPV1). The putative binding modes of cannabitwinol with TRPA1 and TRPM8 were investigated in detail by a molecular docking study using the homology models of both channels.
Assuntos
Canabinoides/química , Canabinoides/farmacologia , Cannabis/química , Canabinoides/biossíntese , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Canal de Cátion TRPA1/efeitos dos fármacos , Canais de Cátion TRPM/efeitos dos fármacos , Canais de Cátion TRPV/efeitos dos fármacos , Temperatura , Canais de Potencial de Receptor Transitório/efeitos dos fármacosRESUMO
Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents "natural libraries" of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC50 of 5.3 µM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.
Assuntos
Diterpenos/síntese química , Diterpenos/farmacologia , Desenho de Fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Betacoronavirus , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , SARS-CoV-2 , Relação Estrutura-AtividadeRESUMO
Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders.
Assuntos
Canabinoides/química , Canabinoides/farmacologia , Cannabis/química , PPAR gama/agonistas , PPAR gama/metabolismo , Células 3T3-L1 , Animais , Metabolismo Energético/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Resistência à Insulina/fisiologia , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Moringa oleifera Lam. is a tropical plant widely used in traditional medicines and as a food supplement. It is characterized by the presence of glucosinolates and isothiocyanates; the stable isothiocyanate 4-[(α-l-rhamnosyloxy)benzyl]isothiocyanate (moringin) has been widely studied for its bioactivity as hypoglycemic, antimicrobial, anticancer and in particular for its involvement in nociception and neurogenic pain. Moringa extracts and pure moringin were submitted to in vitro assays with the somatosensory TRPA1 ion channel, proving that moringin is a potent and effective agonist of this receptor involved in nociceptive function and pain states. Moringin do not activate or activates very weakly the vanilloids somatosensory channels TRPV1,2,3 and 4, and the melastatin cooling receptor TRPM8. The comparison of moringin's activity with other known agonists of natural origin is also discussed.
Assuntos
Isotiocianatos/farmacologia , Moringa oleifera/química , Dor Nociceptiva/tratamento farmacológico , Canal de Cátion TRPA1/genética , Células HEK293 , Humanos , Isotiocianatos/química , Dor Nociceptiva/patologia , Nociceptores/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Córtex Somatossensorial , Canal de Cátion TRPA1/antagonistas & inibidores , Canais de Cátion TRPM/genética , TransfecçãoRESUMO
Sisymbrium officinale (L.) Scop. is a wild common plant of the Brassicaceae family. It is known as "the singers' plant" for its traditional use in treating aphonia and vocal disability. Despite its wide use in herbal preparations, the molecular mechanism of action of S. officinale extracts is not known. The plant is rich in glucosinolates and isothiocyanates, which are supposed to be its active compounds. Some members of this family, in particular allylisothiocyanate, are strong agonists of the transient receptor potential ankyrin 1 (TRPA1) channel, which is involved in the somatosensory perception of pungency as well as in the nociception pathway of inflammatory pain. This study aims to isolate the glucosinolates and isothiocianates from fresh S. officinale to identify the major components and test their activity in in vitro assays with a cloned TRPA1 channel. Samples of cultivated S. officinale have been extracted and the active compounds isolated by column chromatography, HPLC and PTLC. The main components glucoputranjivin, isopropylisothiocyanate and 2-buthylisothiocianate have been tested on TRPA1. The glucosinolates glucoputranjivin and sinigrin turned out to be inactive, while isopropylisothiocyanate and 2-buthylisothiocyanate are potent agonists of TRPA1, with an EC50 in the range of the high potency natural agonists identified so far for this somatosensory channel.
Assuntos
Brassicaceae/metabolismo , Glucosinolatos/metabolismo , Isotiocianatos/metabolismo , Canal de Cátion TRPA1/metabolismo , Brassicaceae/genética , Canal de Cátion TRPA1/genéticaRESUMO
Electrophilic attack to a double bond, the classic trigger of intramolecular isoprenoid cyclizations, is apparently silent in Cannabis and the diversity of the cannabinome can be ultimately traced to the oxidative cyclization of cannabigerolic acid (CBGA, 1a), a process triggered by the generation of an aromatic electrophilic species. To expand the chemical space of the cannabinoid chemotype, we have investigated an oxidative trigger based on the addition of iodine to the terminal isoprenyl double bond of cannabigerol (CBG, 1b), the decarboxylated and thermally stable version of CBGA (1a). Apart from the predictable product of an iodine-induced cascade cyclization (3), also a pair of unprecedented spiranes named spirocannabigerols (4a,b), derived from the formation of an edge-protonated cyclopropyl cation was also formed, along with a product (5) resulting from the incorporation, in a Friedel-Craft fashion, of the reaction solvent (toluene). Biological evaluation of these compounds on six thermo-transient receptor potential channels (TRPs) showed a remodeling of bioactivity compared to GBC, with emphasis on TRPA1 rather than TRPM8.
Assuntos
Canabinoides/metabolismo , Iodo/química , Animais , Canabinoides/química , Ciclização , Células HEK293 , Humanos , Concentração Inibidora 50 , Ratos , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismoRESUMO
Treatment with iodine cleanly converts various p-menthane-type phytocannabinoids and their carboxylated precursors into cannabinol (CBN, 1a). The reaction is superior to previously reported protocols in terms of simplicity and substrate range, which includes not only tricyclic tetrahydrocannabinols such as Δ9-THC (2a) but also bicyclic phytocannabinoids such as cannabidiol (CBD, 3a). Lower homologues from the viridin series (2c and 3c, respectively) afforded cannabivarin (CBV), a non-narcotic compound that, when investigated against a series of ionotropic (thermo-TRPs) biological end-points of phytocannabinoids, retained the submicromolar TRPA1-activating and TRPM8-inhibiting properties of CBN, while also potently activating TRPV2. Treatment with iodine provides an easy access to CBN (1a) from crude extracts and side-cuts of the purification of Δ9-THC and CBD from respectively narcotic Cannabis sativa (marijuana) and fiber hemp, substantially expanding the availability of this compound and, in the case of fiber hemp, dissecting it from narcotic phytocannabinoids.
Assuntos
Agonistas de Receptores de Canabinoides/química , Iodo/química , Canabidiol/química , Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/química , Canabinoides/farmacologia , Canabinol/química , Canabinol/farmacologia , Cannabis/química , Linhagem Celular , Dronabinol/química , Dronabinol/farmacologia , Células HEK293 , Humanos , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismoRESUMO
Phytochemical investigation of the apolar extract obtained from aerial parts of the Iranian endemic plant Echinophora platyloba DC (Apiaceae) resulted in the characterization of the polyacetylene fraction of this plant. This resulted to be composed of the known echinophorins A and B, embedding the very rare α-pyrone terminal, and of the new echinophorin D (3), including also three conjugated triple bonds. The chemical structures of these compounds were secured by detailed inspection of MS and 1D/2D NMR spectra. The isolated polyacteylenes were evaluated for their modulation of six thermo-TRP channels and they revealed a selective activity on TRPA1, an ion channel involved in the mediation of neuropathic and inflammatory pain. This is the first report on the activity of plant polyacetylenes on transient receptor potential (TRP) channels.
Assuntos
Apiaceae/química , Poli-Inos/química , Poli-Inos/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidores , Células HEK293 , Humanos , Irã (Geográfico) , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Canal de Cátion TRPA1/metabolismoRESUMO
A series of twenty resveratrol analogues was synthesized and tested on TRPA1 and TRPV1 channels. None was able to significantly modulate TRPV1 channels. Conversely, most of them exhibited remarkably higher TRPA1 modulating activity than resveratrol. Optimal potency was observed with ortho monoxygenated stilbenes 6 and 17.
Assuntos
Estilbenos/química , Canais de Cátion TRPC/metabolismo , Animais , Cálcio/metabolismo , Células HEK293 , Humanos , Concentração Inibidora 50 , Transporte de Íons/efeitos dos fármacos , Ligação Proteica , Ratos , Resveratrol , Estilbenos/metabolismo , Estilbenos/farmacologia , Canal de Cátion TRPA1 , Canais de Cátion TRPC/química , Canais de Cátion TRPC/genéticaRESUMO
A series of 31 arylboronic acids designed on the basis of the pharmacophore model for a variety of TRPV1 antagonists was prepared and tested on FAAH and TRPV1 channel. Four of them, that is, compounds 3c, 4a, 5a,b acted as dual FAAH/TRPV1 blockers with IC50 values between 0.56 and 8.11µM whereas ten others (compounds 1c,f-i, 2c-f, 4b) inhibited FAAH and activated/desensitized TRPV1.
Assuntos
Amidoidrolases/antagonistas & inibidores , Ácidos Borônicos/farmacologia , Inibidores Enzimáticos/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Amidoidrolases/metabolismo , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
An expeditious isolation method for the cembrane diterpene alcohols incensol (1a) and serratol (2) has been developed from respectively African and Indian frankincense. The two native alcohols and a series of semisynthetic derivatives of incensol were evaluated for transient receptor potential vanilloid 3 (TRPV3) activation and the inhibition of NF-κB, the putative molecular targets underlying the psychotropic and anti-inflammatory activities of incensol acetate (IA, 1b). Serratol (2) was the most potent TRPV3 activator, outperforming by 2 orders of magnitude the reference agonist thymol and by 1 order of magnitude incensol acetate (1b). Acylation, epimerization, and oxidation did not significantly improve the affinity of incensol for TRPV3, while NF-κB inhibition, marginal for both natural alcohols, could be improved by esterification of incensol (1a) with lipophilic acids. Interestingly, incensol (1a) but not IA (1b) was a potent inhibitor of STAT3, raising the possibility that hydrolysis to incensol (1a) might be involved in the in vivo biological activity of IA (1b). Serratol was not amenable to chemical modification, but some marine cembranoids related to the frankincense diterpenoids showed a certain degree of TRPV3-activating properties, qualifying the aliphatic macrocyclic cembrane skeleton as a selective chemotype to explore the pharmacology of TRPV3, a thermo-TRP otherwise resistant to modulation by small molecules.
Assuntos
Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Anti-Inflamatórios não Esteroides/química , Diterpenos/química , Franquincenso/química , Itália , Estrutura Molecular , Fármacos Neuroprotetores/química , Fator de Transcrição STAT3/antagonistas & inibidores , Relação Estrutura-Atividade , Canais de Cátion TRPV/efeitos dos fármacosRESUMO
Fentanyl is a powerful opiate analgesic typically used for the treatment of severe and chronic pain, but its prescription is strongly limited by the well-documented side-effects. Different approaches have been applied to develop strong analgesic drugs with reduced pharmacologic side-effects. One of the most promising is the design of multitarget drugs. In this paper we report the synthesis, characterization and biological evaluation of twelve new 4-anilidopiperidine (fentanyl analogues). In vivo hot-Plate test, shows a moderate antinociceptive activity for compounds OMDM585 and OMDM586, despite the weak binding affinity on both µ and δ-opioid receptors. A strong inverse agonist activity in the GTP-binding assay was revealed suggesting the involvement of alternative systems in the brain. Fatty acid amide hydrolase inhibition was evaluated, together with binding assays of cannabinoid receptors. We can conclude that compounds OMDM585 and 586 are capable to elicit antinociception due to their multitarget activity on different systems involved in pain modulation.
Assuntos
Analgésicos/farmacologia , Carbamatos/análise , Piperidinas/farmacologia , Ureia/análise , Analgésicos/química , Animais , Feminino , Cobaias , Masculino , Camundongos , Piperidinas/química , Ratos , Ratos Wistar , Análise Espectral/métodosRESUMO
Four positively charged compounds, previously shown to produce analgesic activity by interacting with prokineticin receptor or T-type calcium channels, were tested for their ability to inhibit capsaicin-induced elevation of intracellular Ca(2+) in HEK-293 cells stably transfected with the human recombinant TRPV1, with the goal of identifying novel TRPV1 open-pore inhibitors. KYS-05090 showed the highest potency as a TRPV1 antagonist, even higher than that of the open-pore triazine inhibitor 8aA. The latter showed quite remarkable agonist/desensitizer activity at the rat recombinant TRPM8 channel. The activity of KYS-05090 and the other compounds was selective because none of these compounds was able to modulate the rat TRPA1 channel. Open-pore inhibitors of TRPV1 may be a new class of multi-target analgesics with lesser side effects, such as loss of acute pain sensitivity and hyperthermia, than most TRPV1 antagonists developed so far.
Assuntos
Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/metabolismo , Canais de Cátion TRPV/metabolismo , Triazinas/farmacologia , Analgésicos/farmacologia , Animais , Cálcio/metabolismo , Capsaicina/metabolismo , Linhagem Celular , Febre/tratamento farmacológico , Febre/metabolismo , Células HEK293 , Humanos , Dor/tratamento farmacológico , Dor/metabolismo , Quinazolinas/farmacologia , RatosRESUMO
Replacement of the benzylamide motif of synthetic capsaicin (nonivamide, 1c) with a tetrazole moiety was detrimental for TRPV1 binding, but unexpectedly generated a potent and non-electrophilic TRPA1 agonist (4a). Spurred by this observation and by the relatively small number of non-covalent TRPA1 ligands reported so far, the benzylamide-to-tetrazole swap was investigated in the more lipophilic and powerful vanilloids olvanil (1d), rinvanil (1e), and phenylacetylrinvanil (1f). In all cases, the replacement was detrimental for TRPV1 binding, but a clear modulation of TRPA1 activity was observed. These observations show that the capsaicinoid pharmacophore displays orthogonal structure-activity relationships for TRPV1 and TRPA1 binding, and suggest the possibility of obtaining compounds with dual TRPV1/TRPA1 modulatory properties by exploration of the chemical space around the capsaicin motif.
Assuntos
Capsaicina/análogos & derivados , Proteínas do Tecido Nervoso/agonistas , Fármacos do Sistema Sensorial/química , Fármacos do Sistema Sensorial/farmacologia , Tetrazóis/química , Tetrazóis/farmacologia , Canais de Potencial de Receptor Transitório/agonistas , Canais de Cálcio/metabolismo , Capsaicina/química , Capsaicina/farmacologia , Descoberta de Drogas , Células HEK293 , Humanos , Ligantes , Proteínas do Tecido Nervoso/metabolismo , Relação Estrutura-Atividade , Canal de Cátion TRPA1 , Canais de Cátion TRPV/metabolismo , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
A series of structural analogues of the TRPM8 agonist icilin was prepared. The compounds were examined for their ability to exert agonist or antagonist effects in HEK-293 cells expressing the TRPM8 receptor. Most structural modifications of the icilin structure largely met with diminished TRPM8 agonist activity. Cinnamamide 'open-chain' analogs of icilin, however, demonstrated significant antagonistic actions at the TRPM8 receptor. Optimal potency (IC50=73 nM) was observed in the 3-iodo derivative 18l.