Neutral Cannabinoid Receptor
8 -THC with an acetylenic side chain, and VCHR, an
Antagonists
analogue of SR141716A, are neutral CB 1 receptor
There is currently considerable interest in the
antagonists. 2,74 As this evidence is somewhat
possibility of developing potent neutral CB 1 and CB 2
preliminary, particular caution should be exercised
receptor antagonists: i.e. high-affinity ligands for
when using any of these ligands as a pharmacological
CB 1 or CB 2 receptors that lack significant agonist or
tool. There is more complete evidence that another
inverse agonist efficacy. One reason for this is that
SR141716A analogue, NESS 0327, is a neutral CB 1
unlike the CB 1 and CB 2 -selective antagonists/inverse
receptor antagonist. 55 However, this compound is
agonists now available (see previous sections),
currently not commercially available and so has not
a neutral antagonist could be used to distinguish
been much used in cannabinoid research.
between tonic cannabimimetic activity arising from
Radiolabelled Cannabinoid Receptor
ongoing endocannabinoid release onto CB 1 or CB 2
receptors, which it should oppose, and tonic activity
Ligands
arising from the presence of constitutively active CB 1
Tritiated
cannabinoid
receptor
ligands
that
or CB 2 receptors, which it should not. Although no
have been most widely used in binding assays
neutral antagonist that selectively targets the CB 2
or for autoradiography are the CB 1 -selective
receptor has yet been developed, some progress has
[ 3 H]SR141716A (CB 1 K d = 0.19 to 1.24 nM), and
been made on the CB 1 receptor front. Thus, there is
[ 3 H]CP 55,940, [ 3 H]WIN 55,212-2 and [ 3 H]HU 243,
some evidence that 6´´-azidohex-2´´-yne-cannabidiol
all three of which bind more or less equally well
(O-2654), O-2050, a sulphonamide analogue of
to CB 1 and CB 2 receptors. Typical K d values for
Table 3 | Some established and putative non-CB 1 , non-CB 2 targets with which CB 1 /CB 2 receptor agonists
have been postulated to interact at concentrations of 1 µ M or less
Voltage-gated ion channels containing a target
Measured response
CB 1 /CB 2 receptor agonist
Reference
N-type Ca 2+ channels
Ion current (–)
Anandamide
86
T-type Ca 2+ channels
Ion current (–)
Anandamide
86
Na + channels
Ion current (–)
9 -THC, 11-hydroxy- 9 -THC
86
(anandamide, 2-arachidonylglycerol at
> 1 µ M)
Ca 2+ -activated (BK) K + channels
Ion current (P)
Anandamide
86
Other types of voltage-gated K + channels
Ion current (–)
Anandamide
86
Receptors/ligand-gated ion channels containing a target
α 7 nACh channels
Ion current (–)
Anandamide, 2-arachidonylglycerol
86
Glycine receptors
Ion current (–/P)
Anandamide, 2-arachidonylglycerol,
86
9 -THC
NR1A-containing NMDA channels
Ion current (P)
Anandamide
86
5-HT 2 receptors
5-HT binding (+)
Oleamide, HU 210
87
5-HT 3 receptors (5-HT 3A subunit)†
Ion current (–)
9 -THC, WIN 55212-2, anandamide,
88
JWH 015, CP 55,940
TRPV1 receptors
Ion current (A)
Anandamide, methanandamide
86, 88
(not 2-arachidonylglycerol, HU 210,
CP 55,940, WIN 55212-2)
TRPV4 receptors
Ion current (A)
Anandamide
86
Central putative TRPV1-like receptors
Ion current (–)
WIN 55212-2, CP 55,940
89
Central putative non-CB 1 , non-CB 2 , non-TRPV1
Receptor activation (+)
WIN 55212-2, anandamide
90
G-protein-coupled receptors
(not 9 -THC, HU 210, CP 55,940)
Putative non-CB 1 , non-CB 2 , non-TRPV1 neuronal
Receptor activation (+)
9 -THC, cannabinol (not HU 210 or
88
receptors
CP 55,940)
Putative non-I 1 , non-I 2 imidazoline neuronal receptors
Receptor activation (+)
CP 55,940
88
(WIN 55212-2, anandamide at > 1 µ M)
Sites on neuronal transporters
Noradrenaline transporter
Synaptosomal uptake (P)
9 -THC
46
Dopamine transporter
Synaptosomal uptake (P/–)
9 -THC
46
5-HT transporter
Synaptosomal uptake (P/–)
9 -THC
46
A, activation; P, potentiation; (+), increase induced; (–), decrease induced.
†The rank order of potency for antagonism of human 5-hydroxytryptamine (5-HT 3A ) receptors expressed by HEK 293 cells is 9 -THC > WIN 55,212-2 > anandamide
> JWH 015 > CP 55,940. 91
Cannabinol is a classical cannabinoid that exhibits both less affinity for CB 1 receptors and less CB 1 efficacy than 9 -THC (see references 2 and 41).
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