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

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

The cannabinoid receptor family currently includes twotypes:CB1, characterized in neuronal cells and brain, and CB2, characterized in immune cells and tissues. CB1 and CB2 receptors are members of the superfamily of seven-transmembrane-spanning (7-TM) receptors, having a protein structure defined by an array of seven membrane-spanning helices with intervening intracellular loops and a C-terminal domain that can associate with G proteins. Cannabinoid receptors are associated with G proteins of the Gi/o family (Gi1,2 and 3, and Go1 and 2). Signal transduction via Gi inhibits adenylyl cyclase in most tissues and cells, although signaling via Gs stimulates adenylyl cyclase in some experimental models. Evidence exists for cannabinoid receptor-mediated Ca2+ fluxes and stimulation of phospholipases A and C. Stimulation of CB1 and CB2 cannabinoid receptors leads to phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK), p38 MAPK and Jun N-terminal kinase (JNK) as signaling pathways to regulate nuclear transcription factors. The CB1 receptor regulates K+ and Ca2+ ion channels, probably via Go. Ion channel regulation serves as an important component of neurotransmission modulation by endogenous cannabinoid compounds released in response to neuronal depolarization. Cannabinoid receptor signaling via G proteins results from interactions with the second, third and fourth intracellular loops of the receptor. Desensitization of signal transduction pathways that couple through the G proteins probably entails phosphorylation of critical amino acid residues on these intracellular surfaces.

Cannabinoid receptor signaling

ARTICLE I NFO In the last 25 years data has grown exponentially dealing with the discovery of the endocannabinoid system consisting of specific cannabinoid receptors, their endogenous ligands, and enzymatic systems of their biosynthesis and degradation. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity which should help in providing a greater understanding of the physiological role of the endocannabinoid system and perhaps also in a broad number of pathologies. This could lead to advances with important therapeutic potential of drugs modulating activity of endocannabinoid system as hypnotics, analgesics, antiemetics, antiasthmatics, antihypertensives, immunomodulatory drugs, antiphlo- gistics, neuroprotective agents, antiepileptics, agents influencing glaucoma, spasticity and other "movement disorders", eating disorders, alcohol withdrawal, hepatic fibrosis, bone growth, and atherosclerosis. The aim of this review is to highlight distribution of the CB1 and CB2 receptor subtypes in the nervous system and functional involvement of their specific ligands.

https://www.alchimiaweb.com/blogfr/wp-content/uploads/2014/01/Cannabinoid-receptors-1-and-2-CB1-and-CB2-their-distribution-ligands-and.pdf

Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures--a short review.

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.

B. R. Martin

Papers

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

Cannabimimetic Fatty Acid Derivatives: The Anandamide Family and Other “Endocannabinoids”