Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.

https://pharmrev.aspetjournals.org/content/pharmrev/54/2/161.full.pdf

International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors

http://www.student.oulu.fi/~taneliha/15min_Vertailevan_Endokrinologian_opiskelijaesitelma_Endokannabinoidit/Suurin%20osa%20k%E4ytetyist%E4%20artikkeleista/Cannabinoid%20physiology%20and%20pharmacology%2030%20years%20of%20progress.pdf

Cannabinoid physiology and pharmacology: 30 years of progress

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(15)00034-6.pdf

Endocannabinoid signaling at the periphery: 50 years after THC

N-Palmitoyl-ethanolamine (PEA) is an anti-inflammatory component of egg yolk that is usually employed for the prevention of respiratory apparatus virus infection and then frequently used for its efficient anti-inflammatory and analgesic effects in experimental models of visceral, neuropathic, and inflammatory diseases. Nevertheless, data of its use in animal or human therapy are still scarce and further studies are needed. Herein, we report the biological evaluation of a small library of N-palmitoyl-ethanolamine analogues or derivatives, characterized by a protected acid function (either as palmitoyl amides or hexadecyl esters), useful to decrease their hydrolysis rate in vitro and prolong their biological activity. Two of these compounds—namely phenyl-carbamic acid hexadecyl ester (4) and 2-methyl-pentadecanoic acid (4-nitro-phenyl)-amide (5)—have shown good anti-inflammatory and antioxidant properties, without affecting the viability of J774A.1 macrophages. Finally, crystals suitable for X-ray analysis of compound 4 have been obtained, and its solved crystal structure is here reported. Our outcomes may be helpful for a rational drug design based on new PEA analogues/derivatives with improved biological properties.

https://www.mdpi.com/1420-3049/22/4/616/pdf

Anti-Inflammatory, Antioxidant and Crystallographic Studies of N-Palmitoyl-ethanol Amine (PEA) Derivatives

https://www.cell.com/cell-metabolism/pdf/S1550-4131(13)00103-4.pdf

The Endocannabinoid System in Energy Homeostasis and the Etiopathology of Metabolic Disorders

In the late 1990's, a series of experiments carried out independently in two laboratories led to establish an important connection between the function of the endocannabinoids, which, as exemplified in this special issue, is per se very complex and ubiquitous in animals, and that of the transient receptor potential (TRP) channels, a large family of plasma membrane cation channels involved in several mammalian and non-mammalian physiological and pathological conditions, overlapping only in part with those in which the cannabinoid receptors participate. These experiments were initially based on the observation that the endocannabinoid anandamide and the xenobiotic ligand of TRP channels of V1 type (TRPV1), capsaicin, are somehow chemically similar, both compounds being fatty acid amides, as are also synthetic activators of these channels and inhibitors of anandamide cellular re-uptake. As discussed in this article, the same type of "chemical thoughts" led to the discovery of N-arachidonoyl-dopamine, an endogenous ligand of TRPV1 channels that behaves also an endocannabinoid. The overlap between the ligand recognition properties of some TRP channels and proteins of the endocannabinoid system, namely the cannabinoid receptors and the proteins and enzymes catalyzing anandamide cellular re-uptake and hydrolysis, is being actively explored through the rational design and synthesis of new endocannabinoid-based drugs with multiple mechanisms of action. These aspects are discussed in this review article, together with the possible functional and pharmacological consequences of endocannabinoid-TRP channel interactions.

Endocannabinoids as regulators of transient receptor potential (TRP) channels: A further opportunity to develop new endocannabinoid-based therapeutic drugs.

In agreement with the highly lipophilic nature of (-)-Δ 9 -tetrahydrocannabinol, all the endogenous ligands of cannabinoid receptors identified so far are derivatives of long chain fatty acids. N- Arachidonoylethanolamine (anandamide) and some of its polyunsaturated congeners have been found in mammalian brain and shown to activate the CB1 and, with a lower efficacy, CB2 cannabinoid receptor subtypes. More recently, 2-arachidonoylglycerol (2-AG), a widespread intermediate in the metabolism of phosphoglycerides, diacylglycerols and triglycerides, was also found to activate the cannabinoid receptors. The capability of palmitoylethanolamide, an anti-inflammatory metabolite, to activate CB2-like receptors is still being debated. Here we review: 1) the metabolic pathways suggested so far to underlie the biosynthesis and inactivation of anandamide and 2-AG, and 2) the current knowledge of the chemical bases for the interactions of anandamide and 2-AG with proteins of the 'endogenous cannabinoid system' characterized so far, i.e. the CB1 and CB2 receptor subtypes, the membrane 'anandamide carrier', which facilitates anandamide diffusion into cells, and the enzyme 'fatty acid amide hydrolase', which catalyzes anandamide and, to a certain extent, 2-AG hydrolysis in vivo.

Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids.

Objective: Preparation and characterization of anandamide (N-arachidonoyl-ethanolamine, AEA) loaded polycaprolactone nanoparticles (PCL NP) as a research tool to clarify the presence of an AEA transporter in cell membranes and to avoid AEA plastic adsorption and instability.Materials and methods: High performance liquid chromatography and light scattering were used to determine encapsulation efficiency, particle size, drug release, permeability and stability.Results: A high encapsulation efficiency 96.05 ± 1.77% and a particle size of 83.52 ± 21.38 nm were obtained. Nearly 40% of AEA remained in the NP after a 99.9% dilution and only 50% was released after 24 h at 37°C with a 99% dilution. PCL NP prevented the adsorption of the drug to polypropylene or polystyrene, but not to acrylic multiwell plates. Drug permeability through artificial membranes was low (10−7 to 10−8 cm/s) and was affected by the presence of NP. NP increased AEA stability in suspension (drug half-life 431 h vs. 12 h) and freeze-dried wi...

De Petrocellis L

Papers

Endocannabinoids as regulators of transient receptor potential (TRP) channels: A further opportunity to develop new endocannabinoid-based therapeutic drugs.

Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids.

Anandamide-loaded nanoparticles: Preparation and characterization