Cannabinoid Receptor Ligands
K + and L-type Ca 2+ channels, CYP enzymes,
Figure 9 | Structures of (–)-cannabidiol (CBD),
acyltransferase, a neuronal non-CB 1 site of action
(–)- 9 -tetrahydrocannabivarin ( 9 -THCV), O-1602,
in the mouse vas deferens, and the putative
abnormal-cannabidiol (abn-CBD) and O-1918
non-CB 1 , non-CB 2 , non-TRPV1 “abnormal-CBD
receptor” that has been postulated to be present
7
in tissues such as mesenteric arteries and in
1
6
2
OH
microglial cells; 2,88,123
OH
3'
H
5
2'
4'
4
3
  • a set of CBD analogues (Figure 9) which lack
  • H
    5'
    significant affinity for the CB 1 receptor and behave
    9
    8
    OH
    6'
    1''
    3''
    5''
    O
    as agonists (abnormal-CBD and O-1602) or
    antagonists (O-1918) for the putative abnormal-
    9 -THCV
    CBD receptor; 2,88,96
  • the endogenous compound, N -arachidonoyl- L -
  • OMe
    serine (Figure 10), which may be an endogenous
    agonist for the abnormal-CBD receptor as it
    OH
    appears to activate this putative receptor when
    OH
    OH
    OMe
    OH
    added exogenously (EC 50 = 550 or ca 1200 nM),
    and which binds only weakly to CB 1 receptors
    O-1602
    (K i > 10 µ M) and does not bind to CB 2 or TRPV1
    receptors at concentrations of up to 30 µ M; 124
    (Bold Link Text Denotes Compounds Available From Tocris)
  • the
  • anandamide/capsaicin
    structural
    hybrid,
    N -vanillyl arachidonyl amide (arvanil ; Figure 10),
    compounds so far found to inhibit the cellular uptake
    which binds to TRPV1 receptors at concentrations
    of anandamide do so by targeting an anandamide
    in the low nanomolar range, binds to CB 1 receptors
    transport protein or by attenuating FAAH-mediated
    and inhibits the cellular uptake of anandamide at
    metabolism of anandamide to cause an intracellular
    concentrations in the low micromolar range and
    accumulation of this fatty acid amide that is sufficient
    may also have one or more as yet unidentified
    to oppose its entry into the cell by diffusion. 25-27
    non-CB 1 , non-TRPV1 sites of action; 125,126
    Some Other Notable Ligands
  • the synthetic indole derivatives, Org 27569,
  • In addition to the CB 1 and CB 2 receptor ligands
    Org 29647
    and
    Org
    27759
    (Figure
    11),
    already discussed there are a number of other
    experiments with which have revealed the
    compounds that deserve mention either because
    presence of an allosteric site on the cannabinoid
    they can modulate some effects of established
    CB 1 receptor that constitutes a new target through
    CB 1 /CB 2 receptor agonists through seemingly novel
    which CB 1 receptor activation by endogenously
    mechanisms or because they share the apparent
    released endocannabinoids could be modulated,
    ability of such agonists to target certain putative non-
    for example to combat inflammatory pain, obesity
    CB 1 , non-CB 2 receptors. These compounds are:
    or nicotine dependence. 127
  • the plant cannabinoid, 9 -tetrahydrocannabivarin
  • (Figure 9), which displaces [ 3 H]CP 55,940 from
    Figure 10 | Structures of arvanil and
    CB 1 and CB 2 receptors at concentrations in
    N -arachidonoyl- L -serine
    the low nanomolar range (K i = 75.4 and 62.8
    nM respectively) and behaves as a CB 1 and
    CB 2 receptor competitive antagonist, exhibiting
    O
    greater potency against CP 55,940 in the mouse
    OMe
    N
    isolated vas deferens and in membranes obtained
    H
    OH
    from human CB 2 -transfected cells (apparent K B =
    10 nM) than in mouse brain membranes (apparent
    K B = 93 nM); 121
  • the
  • non-psychoactive
    plant
    cannabinoid,
    OH
    O
    (–)-Cannabidiol (CBD; Figure 9), which lacks
    N
    CO 2 H
    significant affinity for CB 1 or CB 2 receptors, has
    H
    therapeutic potential (e.g. as an anti-inflammatory
    agent), possesses anti-oxidant/neuroprotective
    properties and, at sub-micromolar concentrations,
    N -Arachidonoyl- L -serine
    activates blocks or inhibits a number of established
    or putative pharmacological targets that include an
    adenosine transporter 122 and also delayed rectifier
    (Bold Link Text Denotes Compounds Available From Tocris)
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