Endocannabinoids noladin ether

Shoemaker JL, Joseph BK, Ruckle MB, Mayeux PR, Prather PL (2005) The endocannabinoid noladin ether acts as a full agonist at human CB2 cannabinoid receptors. J Pharmacol Exp Ther... 

Juntunen, J., Vepsalainen, J., Niemi, R., Laine, K. and Jarvinen, T. (2003) Synthesis, in vitro evaluation, and intraocular pressure effects of water-soluble prodrugs of endocannabinoid noladin ether. Journal of Medicinal Chemistry, 46, 5083-5086. 

The novel endocannabinoid noladin ether was recently identified by Hanus et al. (2001). Subsequently, its existence in brain was reported by Fezza et al. (2002), but Oka et al. (2003) were unable to detect the compound in the brains of any of several mammalian species by gas chromatography/mass spectrometry. Noladin ether was reported to occur in relatively high amounts in dissected thalamus, but its localization to somatosensory areas of thalamus has not been established. It was reported to occur in much lower amounts in spinal cord (Fezza et al. 2002). Hanus et al. (2001) showed that the compound produces analgesic effects in the hot plate test following systemic administration in mice (20 mg/kg, i.p.). However, as with 2-AG, experiments have not been carried out to determine whether its effects were due to an action at CBRs. More work is needed to verify the formation of this compound in vivo and its potential role in pain modulation. 

Noladin ether (3) was recently isolated from porcine brain [16] and found to bind to the CBi receptor (/fj = 21.2 nM), to bind weakly to the CB2 receptor K, > 3 /iM) and it causes typical cannabinoid-like effects such as sedation, hypothermia, intestinal immobility and mild antinociception in mice [16]. This endocannabinoid had previously been synthesised independently by both Mechoulam and co-workers [176] and Sugiura et al. [173]. SAR studies of this endocannabinoid are lacking in the literature, however, a recent publication highlighted the importance of the tetra-unsaturated C20 chain... 

Arachidonyl glyceryl ether (noladin ether), isolated from porcine brain, is an example of a third, ether-type endocannabinoid. The name is derived from the Hebrew word nolad, what means to be born. The... 

Fezza, F., Bisogno, T., Minassi, A., Appendino, G., Mechoulam, R., and Di Marzo, V. (2002). Noladin ether, a putative novel endocannabinoid Inactivation mechanisms and a sensitive method for its quantification in rat tissues. FEBS Lett. 513, 294 298. 

Paldyova E, Bereczki E, Santha M, Wenger T, Borsodi A, Benyhe S (2008) Noladin ether, a putative endocannabinoid, inhibits mu-opioid receptor activation via CB2 cannabinoid receptors. Neurochem Int 52 321-328... 

Very little is known about the biosynthesis of the three most recently proposed endocannabinoids, 2-AGE, virodhamine and NADA. Regarding 2-AGE (noladin ether), this compound was previously identified in pig brain (Hanus et al. 2001) and in some rat tissues and brain areas (Fezza et al. 2002) by using mass-spectrometric (MS) methods coupled to chromatographic separations. However, a recent study cast some doubt on the actual existence of 2-AGE in mammalian brain tissue (Oka et al. 2003). At the time of this study it was already known that (1) the only acyl ethers to have been detected in animals before the discovery of 2-AGE were 2-acyl ethers (e.g. alkenyl ethers such as platelet activating factor and plasmalogens) (2) there was no evidence for the existence of any enzyme catalysing the formation... 

Appendino G, Ligresti A, Minassi A, Daddario N, Bisogno T, Di Marzo V (2003) Homologues and isomers of noladin ether, a putative novel endocannabinoid interaction with rat cannabinoid CB(1) receptors. Bioorg Med Chem Lett 13 43-46... 

Ralevic V, Duncan M, Milins P, Smart D, Wright J, Kendall D (2004) Noladin ether, a putative endocannabinoid, attenuates sensory neurotransmission in the rat isolated mesenteric arterial bed via a non CB1/CB2 Gi/oUnked receptor. Br J Pharmacol 142 509-518... 

The subsequent discovery of the endocannabinoids, arachidonoylethanolamine (anandamide) (Devane et al. 1992b Hanus et al. 1993) and 2-arachidonoyl glycerol (2-AG) (Di Marzo 1998 Mechoulam et al. 1995 Stella et al. 1997) has led to a better understanding of the physiological and biochemical roles of the endocannabinoid system. 2-Arachidonyl glyceryl ether, also known as noladin ether (Hanus et al. 2001), has been proposed as a representative of a third endocannabinoid class. However, noladin ether s pathway of formation has not been characterized and its occurrence in the normal brain has been questioned (Oka et al. 2003). 

An ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether, 54, Fig. 13) was reported to be isolated from porcine brain (Hanus et al. 2001). Noladin ether was found to bind selectively to the CBi receptor (Kj = 21.2 nM) and cause sedation, hypothermia, intestinal immobility, and mild antinociception in... 

Seven putative endocannabinoids have been identified (1) anandamide, (2) dihomo-y-linolenoylethanolamide (HEA), (3) docosatetraenoylethanolamide (DEA), (4) 2-AG, (5) noladin ether, (6) virodhamine, and (7) N-arachidonoyldopamine (NADA). The roles of these novel putative endogenous compounds in pain and inflammation have been a recent focus of investigations. The sections above, which described the... 

FIGURE 3.4 Effect of endocannabinoids on AMPA glutamate receptor. In Xenopus oocytes expressing the recombinant rat GluIT3 subunit of AMPA receptor, anandamide, 2-arachidonyl glycerol, and noladin ether inhibited kainate-activated currents. The order of potency of the endocannabinoids in inhibiting receptor currents in oocytes was anandamide > 2-arachidonyl glycerol > noladin ether. 

Finally, the effect on VR1 of the other two proposed endocannabinoids, virodhamine and noladin ether, were assessed in two different preliminary studies (Duncan et al., 2003 Gough et al., 2003). Both compounds were found to be inactive. 

FIGURE 8.1 The principal endogenous cannabinoids. Anandamide and 2-arachidonyl glycerol (2-AG) are the most well-studied endocannabinoids however, conjugates with other fatty acids such as palmitic and eicosapenteneoic acid are well known. Novel structures such as virodhamine and noladin ether have also been reported. Arachidonic acid derivatives with other molecules such as dopamine (NADA) and glycine (NAGly) are also known. 

At this point, it is premature to ascribe all of these synaptie effeets to a single endocannabinoid molecule (2-AG, anandamide, noladin ether, ete.). Although evidenee in the hippocampus seems to... 

FIGURE 14.1 Four endogenous substances suggested as being endocannabinoids anandamide (N-arachi-donoylethanolamine), 2-AG (2-arachidonoylglycerol), noladin ether (2-arachidonylglyceryl ether), and virodhamine (O-arachidonoylethanolamine). The stracture of the principal cannabinoid of plant origin, A -THC (A -tetrahydrocannabinol), is inserted. 

The more stable analogs of both 2-AG (noladin ether, also a putative endocannabinoid) and anandamide (methanandamide) do not induce vomiting (Darmani, 2002b and Dar-mani, unpublished findings). 

The mammalian endocannabinoid family inclndes fonr lipid Af-fatty acyl-ethanolamines (NAEs), two Af-acyl-dopamines, a lipid ester, and a lipid ether. The NAEs are Af-arachidonoyl ethanolamine (anan-damide, AEA) (Devane et al., 1992), docosatetraenoyl-ethanolamide and di-homo-y-hnolenoyl-ethanolamide (Hanus et al., 1993), and O-arachidonoyl ethanolamide (virodhamine) (Porter et al., 2002). The Af-acyl-dopamines are Af-arachidonoyl-dopamine (NADA) and Af-oleoyl-dopamine (Hnang et al., 2002). The lipid ester is sn-2 arachidonoyl glycerol (2-AG) (Mechonlam et al., 1995 Sugiura et al., 1995). The lipid ether is sn-2 arachidonoyl glyceryl ether (noladin ether) (Hanus et al., 2001). 

Very httie is known of the biosynthetic pathways of the other putative endocannabinoids, i.e., noladin ether, virodhamine, and ATarachidonoyl-dopamine (NADA). Although the actual occurrence of noladin ether in mammalian tissues is stUl controversial (Hanus et al., 2001 Fezza et al., 2002 Oka et al., 2003), also because of the lack of a working hypothesis regarding a plausible biosynthetic route for a 2-glyceryl ether, the formation of virodhamine has been related to that of AEA, from which the compound can be derived in a nonenzymatic reaction (Markey et al., 2000). In the case of NADA, preliminary data from our laboratory seem to rule out one of the two possible original routes proposed for this compoimd, i.e., that it might be derived from the action on ATarachidonoyl-tyrosine... 

In 1992 an arachidonic acid ethanolamide derivative (67, Fig. 8) isolated from porcine brain and characterized as an endogenous ligand for the cannabi-noid receptors was named anandamide (75). It was then followed by the discovery of two other endocannabinoids 2-AG (76-78) (68, Fig. 8) and 2-arachi-donoylglyceryl ether (79) (noladin ether, 69, Fig. 8). Anandamide is a highly... 

Noladin ether (2-arachidonoyl glycerol ether) is another putative endocannabinoid that also possesses intestinal anlitransit properties. Although 2-AG is also present both in small intestine and colon, its in vivo effects on intestinal motility have not yet been investigated. 

A third type of endocannabinoid is noladin ether (2-arachidonylglyceryl ether) (Figure 1), which was recently isolated from porcine brain (Hanus et al, 2001). In contrast to the chemical nature of anandamide (an amide) and 2-AG (an ester), this endocannabinoid is an ether. Apart from the structural differences, noladin ether also differs from anandamide and 2-AG in its cannabinoid receptor binding. It binds to the CBj cannabinoid receptor (K = 21.2 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. However, in contrast to anandamide and 2-AG it binds very weakly to the CB receptor (K. > 3000 nM). 

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