Cannabinoid ligand

Since the discovery of anandamide in 1992, a number of studies have examined its pharmacological properties. Although its roles are still elusive, a plethora of data supports the initial postulate that anandamide is the major endogenous cannabinoid ligand. As mentioned earlier, anandamide binds to CB1 from brain preparations and displaces various well-... 

All the foregoing pharmacological effects of anandamide, in conjunction with the well-documented existence of specific systems for its biosynthesis, catabolism, and cellular reuptake to be discussed shortly, suggest that anandamide is indeed the endogenous cannabinoid ligand. The other two less studied A -acylethanolamide endocannabinoids and also 2-AG may serve similar functions. The differential roles of each of these four endocannabinoids are still unclear. 

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Paria BC, Das SK, Dey SK. The preimplantation embryo is a target for cannabinoid ligand-receptor signaling. Proc Natl Acad Sci USA 1996 92 9430-9464. 

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The identification of a specific cannabinoid receptor in the brain suggested the existence of a brain cannabinoid ligand. It seemed to us quite unacceptable that the brain will waste its energy to synthesize a receptor (in high concentrations) in order to bind a constituent of a plant. The only reasonable assumption which could be made was that the brain produces a neuronal mediator, a specific compound which binds to and activates the cannabinoid receptor. The plant cannabinoid, J9-THC, by structural coincidence happens to bind to the same receptor. In the late 1980 s, several groups initiated work aimed at the discovery of such a brain constituent. 

The existence of a peripheral cannabinoid receptor (CB2) led us to investigate the possibility that peripheral cannabinoid ligands, distinct from the... 

The existence of a receptor and the high structural requirements for cannabinoid activity indicate the possible presence of a specific endogenous cannabinoid ligand. 

The CB2 gene has been associated with the risk for celiac disease [299], hepatic anomalies [300, 301], osteoporosis [302-304], and drug addiction [305]. An endophenotype consisting of reduced immune modulation may underlie some of these conditions. Risk for immunological compromise may be associated with the CB2 variants [298] suggesting that novel cannabinoid ligands could be developed to reverse this effect [304],... 

Kapur A, Zhao P, Sharir H et al (2009) Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. J Biol Chem 284 29817-29827... 

Begg M, Mo F-M, Offertaler L, Bdtkai S, Pacher P, Razdan RK, Lovinger DM, Kunos G (2003) G protein-coupled endothelial receptor for atypical cannabinoid ligands modulates a Ca2-i--dependent K-i- current. J Biol Chem 278 46188-46194... 

Khanolkar AD, Abadji V, Lin S, HUI WAG, Taha G, Abouzid K, Meng Z, Fan P, Makriyannis A (1996) Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand. J Med Chem 39 4515-4519... 

Wrobleski ST, Chen P, Hynes J, Lin S, Norris DJ, Pandit CR, Spergel S, Wu H, Tokarski JS, Chen X, Gillooly KM, Kiener PA, McIntyre KW, Patil-Koota V, Shuster DJ, Turk LA, Yang G, Leftheris K (2003) Rational design and synthesis of an orally active indolopyridone as a novel conformationally constrained cannabinoid ligand possessing antiinflammatory properties. J Med Chem 46 2110-2116... 

Anandamide produces the full range of behavioral effects (antinociception, catalepsy, and impaired locomotor activity) in CBi receptor knockout mice (Di Marzo et al. 2000). Furthermore, anandamide-stimulated GTPyS activity can be elicited in brain membranes from these mice (Breivogel et al. 2001). These effects were not sensitive to inhibition by SR141716A. Interestingly, of all cannabinoid ligands tested, only WIN 55,212-2 elicited GTPyS activity in CBi knockout mice. This same phenomenon has also been demonstrated in a second strain of CBi receptor knockout mice (Monory et al. 2002). 

Different evidence suggests that the endocannabinoid system plays an important role in the regulation of emotional-like behaviour. Thus, the CBi cannabinoid receptor is widely distributed in limbic and cortical areas involved in the control of emotion. The administration of cannabinoid ligands produces emotional-like responses in different behavioural paradigms. Furthermore, cannabinoids also exert a modulatory role on the activity of the hypothalamic-pituitary adrenal axis (HPA), and these compounds modulate the release of several neurotransmitters involved in emotional behaviour, including CCK and GABA,... 

Wilson Rl, NicoU RA (2002) Endocannabinoid signaling in the brain. Science 296 678-682 Winsauer PJ, Lambert P, Moerschbaecher JM (1999) Cannabinoid ligands and their effects... 

Fig. 1. Established and newly proposed endocannabinoids. Chemical structures ofthe five endogenous cannabinoid ligands identified so far...

Khanolkar AD, Makriyannis A (1999) Structure-activity relationships of anandamide, an endogenous cannabinoid ligand. Life Sci 65 607-616... 

Mechoulam R, Ben Shabat S, Hanus L, Fride E, Vogel Z, Bayewitch M, Sulcova AE (1996) Endogenous cannabinoid ligands-chemical and biological studies. J Lipid Mediat CeU Signal 14 45-49... 

Tius MA, Busch-Petersen J, Marris AR (1997) Synthesis of abifunctional cannabinoid ligand. J Chem Soc Chem Commun 19 1867-1868... 

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