Noladin ether

ViRODHAMINE----ENDOGENOUS CANNABINOID WITH ANTAGONIST PROPERTIES 

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The best studied of the endocarmabinoids are anandamide (A -arachidonyl-ethanolamine, AEA)(1) and 2-arachidonylglycerol (2-AG)(2). Anandamide was first identified from porcine brain extracts by Devane and co-workers in 1992 [13], while 2-AG was first reported in 1995 to have been isolated from canine gut [14] and rat brain [15]. More recently, noladin ether (2-arachidonyl-glyceryl ether, 2-AGE)(3) [16], virodhamine (D-arachidonyl-ethanolamine)(4) [17] and A-arachidonyl-dopamine (NADA)(5) [18] were proposed as endogenous ligands for the cannabinoid receptors. In a subsequent publication, the authors failed to detect noladin ether in mammalian brains and questioned the relevance of this compound as an endocarmabinoid [19]. Anandamide, noladin ether and NADA have functional selectivity for CBi receptors, virodhamine is CB2 selective and 2-AG is essentially non-selective. 

The biosyntheses of anandamide and 2-AG have been studied in depth [10]. These compounds appear to be synthesised on demand in response to certain stimuli, rather than being stored in cells. Little is known regarding the biosynthesis of noladin ether, virodhamine or NADA. 

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... 

Oka S, Tsuchie A, Tokumura A., Muramatsu M, Suhara Y, Takayama H, Waku K, Sugiura T, Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species, JNeurochem 85 ... 

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... 

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... 

The physiochemical properties of noladin ether (164) were successfully improved by introducing a phosphate moiety to the structure. High water solubility and chemical stability, together with a rapid quantitative enzymatic hydrolysis in vitro and the ability to reduce lOP in vivo, prove that the phosphate esters (165) and (166) are promising prodrug candidates of end-ocannabinoid noladin ether (Figure 26). ... 

Figure 20.1 Noladin ether (2), a cannabinoid CB1 receptor agonist, and its monophosphate prodrug (1) [22, 23],...

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. 

In addition to actions at cannabinoid receptors, AEA, 2AG, virodhamine, noladin ether, and NADA also act at the vanilloid receptor (transient receptor potential vanilloid type 1 TRPV1 previously know as VRl), a ligand-gated ion channel that is a member of the transient receptor potential (TRP) ion channel family (recently reviewed by Di Marzo et al. 2002). In addition, zl -THG and cannabinol at high (20 pM) concentrations have recently been identified as agonists at another TRP, the ANKTMl channel (Jordt et al. 2004). These findings raise the possibility that the TRP channels maybe ionotropic cannabinoid receptors. 

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). 

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