Diacylglycerol (DAG) lipase activity is required for axonal growth during development and for retrograde synaptic signaling at mature synapses. This enzyme synthesizes the endocannabinoid ...2-arachidonoyl-glycerol (2-AG), and the CB1 cannabinoid receptor is also required for the above responses. We now report on the cloning and enzymatic characterization of the first specific sn-1 DAG lipases. Two closely related genes have been identified and their expression in cells correlated with 2-AG biosynthesis and release. The expression of both enzymes changes from axonal tracts in the embryo to dendritic fields in the adult, and this correlates with the developmental change in requirement for 2-AG synthesis from the pre- to the postsynaptic compartment. This switch provides a possible explanation for a fundamental change in endocannabinoid function during brain development. Identification of these enzymes may offer new therapeutic opportunities for a wide range of disorders.
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.
Palmitoylethanolamide (PEA) is an endogenous anti-inflammatory lipid mediator and a widely used nutraceutical. In this study, we designed, realized, and tested a drug-carrier conjugate between PEA ...(the active drug) and glucuronic acid (the carrier). The conjugate, named GLUPEA, was characterized for its capability of increasing PEA levels and exerting anti-inflammatory activity both in vitro and in vivo. GLUPEA treatment, compared to the same concentration of PEA, resulted in higher cellular amounts of PEA and the endocannabinoid 2-arachidonoyl glycerol (2-AG), and increased 2-AG-induced transient receptor potential vanilloid type 1 (TRPV1) channel desensitization to capsaicin. GLUPEA inhibited pro-inflammatory monocyte chemoattractant protein 2 (MCP-2) release from stimulated keratinocytes, and it was almost as efficacious as ultra-micronized PEA at reducing colitis in dinitrobenzene sulfonic acid (DNBS)-injected mice when using the same dose. GLUPEA is a novel pro-drug able to efficiently mimic the anti-inflammatory and endocannabinoid enhancing actions of PEA.
Four long‐chain, linear fatty acid dopamides (N‐acyldopamines) have been identified in nervous bovine and rat tissues. Two unsaturated members of this family of lipids, N‐arachidonoyl‐dopamine (NADA) ...and N‐oleoyl‐dopamine, were shown to potently activate the transient receptor potential channel type V1 (TRPV1), also known as the vanilloid receptor type 1 for capsaicin. However, the other two congeners, N‐palmitoyl‐ and N‐stearoyl‐dopamine (PALDA and STEARDA), are inactive on TRPV1. We have investigated here the possibility that the two compounds act by enhancing the effect of NADA on TRPV1 (‘entourage’ effect).
When pre‐incubated for 5 min with cells, both compounds dose‐dependently enhanced NADA's TRPV1‐mediated effect on intracellular Ca2+ in human embryonic kidney cells overexpressing the human TRPV1. In the presence of either PALDA or STEARDA (0.1–10 μM), the EC50 of NADA was lowered from ∼90 to ∼30 nM.
The effect on intracellular Ca2+ by another endovanilloid, N‐arachidonoyl‐ethanolamine (anandamide, 50 nM), was also enhanced dose‐dependently by both PALDA and STEARDA. PALDA and STEARDA also acted in synergy with low pH (6.0–6.7) to enhance intracellular Ca2+ via TRPV1.
When co‐injected with NADA (0.5 μg) in rat hind paws, STEARDA (5 μg) potentiated NADA's TRPV1‐mediated nociceptive effect by significantly shortening the withdrawal latencies from a radiant heat source. STEARDA (1 and 10 μg) also enhanced the nocifensive behavior induced by carrageenan in a typical test of inflammatory pain.
These data indicate that, despite their inactivity per se on TRPV1, PALDA and STEARDA may play a role as ‘entourage’ compounds on chemicophysical agents that interact with these receptors, with possible implications in inflammatory and neuropathic pain.
British Journal of Pharmacology (2004) 143, 251–256. doi:10.1038/sj.bjp.0705924
Tetrahydroisoquinoline derivatives containing embedded urea functions were identified as selective TRPM8 channel receptor antagonists. Structure–activity relationships were investigated, with the ...following conclusions: (a) The urea function and the tetrahydroisoquinoline system are necessary for activity. (b) Bis(1-aryl-6,7dimethoxy-1,2,3,4-tetrahydroisoquinolyl)ureas are more active than compounds containing one tetrahydroisoquinoline ring and than an open phenetylamine ureide. (c) Trans compounds are more active than their cis isomers. (d) Aryl substituents are better than alkyls at the isoquinoline C-1 position. (e) Electron-withdrawing substituents lead to higher activities. The most potent compound is the 4-F derivative, with IC50 in the 10–8 M range and selectivities around 1000:1 for most other TRP receptors. Selected compounds were found to be active in reducing the growth of LNCaP prostate cancer cells. TRPM8 inhibition reduces proliferation in the tumor cells tested but not in nontumor prostate cells, suggesting that the activity against prostate cancer is linked to TRPM8 inhibition.
The endocannabinoid anandamide is able to interact with the transient receptor potential vanilloid 1 (TRPV1) channels at a molecular level. As yet, endogenously produced anandamide has not been shown ...to activate TRPV1, but this is of importance to understand the physiological function of this interaction. Here, we show that intracellular Ca2+ mobilization via the purinergic receptor agonist ATP, the muscarinic receptor agonist carbachol or the Ca2+‐ATPase inhibitor thapsigargin leads to formation of anandamide, and subsequent TRPV1‐dependent Ca2+ influx in transfected cells and sensory neurons of rat dorsal root ganglia (DRG). Anandamide metabolism and efflux from the cell tonically limit TRPV1‐mediated Ca2+ entry. In DRG neurons, this mechanism was found to lead to TRPV1‐mediated currents that were enhanced by selective blockade of anandamide cellular efflux. Thus, endogenous anandamide is formed on stimulation of metabotropic receptors coupled to the phospholipase C/inositol 1,4,5‐triphosphate pathway and then signals to TRPV1 channels. This novel intracellular function of anandamide may precede its action at cannabinoid receptors, and might be relevant to its control over neurotransmitter release.
X=O, NH; R=CH3, Aryl, Aralkyl, OAryl, NHAryl, NHAlkyl. Display omitted
A series of thirty-six geraniol, nerol, citronellol, geranylamine, and nerylamine derivatives was synthesized and tested on ...TRPA1, TRPM8, and TRPV1 channels. Most of them acted as strong modulators of TRPA1 channels with EC50 and/or IC50 values <1μM. None was able to significantly activate TRPM8 channels, while thirteen of them behaved as ‘true’ TRPM8 antagonists. Little or no effect was generally observed on TRPV1 channels. Some of the compounds examined, that is, compounds 1d,g,n, 2c,d,h,i,o, 3b,e exhibited an appreciable selectivity for TRPA1 subtype.
: Waldheimia glabra (Decne.) Regel is a wild plant from the Himalayan Mountains, commonly known as Smooth Ground Daisy. This plant is traditionally used by local populations in religious rituals ...(incense) or in traditional herbal medicine to treat skin diseases, headache, joint pain and fever. In literature few data are available on the investigation of this aromatic plant.
The present work aims at deepening knowledge about the chemical composition of W. glabra extracts and incense, as well as its activity on TRP ion channels.
Extracts and incense of W. glabra were analyzed by using HS-SPME GC/MS, GC/MS and NMR analysis. Tests on the activity of W. glabra extracts and isolated compounds (+)-ludartin 1 and B-ring-homo-tonghaosu 2 on TRP channels were also performed.
Some extracts and pure compounds from W. glabra showed an interesting activity in terms of efficacy and potency on rat TRPA1, an ion channel involved in several sensory mechanisms, including pungency, environmental irritation and pain perception. Activity is discussed and compared with that of other known TRPA1 natural agonists with different chemical structures. All compounds showed only a negligible inhibition activity on rat TRPM8 ion channel.
Our findings demonstrate that W. glabra is involved in the receptor activation mechanism and therefore represents a new natural product potentially useful in pharmaceutical and agrifood research.
Comparison between TRPA1’s potency of natural compounds and a sesquiterpene lactone structure. Display omitted
Leucettamols, bifunctionalized sphingoid-like compounds obtained from a marine sponge Leucetta sp., act as non-electrophilic activators of the TRPA1 channel and potent inhibitors of the ...icilin-mediated activation of the TRPM8 channel, while they are inactive on CB₁, CB₂ and TRPV1 receptors. Leucettamols represent the first compounds of marine origin to target TRPA1 and the first class of natural products to inhibit TRPM8 channels. The preparation of a small series of semi-synthetic derivatives revealed interesting details on the structure-activity relationships within this new chemotype of simple acyclic TRP modulators.
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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=73nM) was observed in the 3-iodo derivative 18l.
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