Cannabinoid Receptor Ligands
One major practical difficulty associated with
cannabinoid research, both in vivo and in vitro , is
JWH 133, Potent and Selective CB 2
the high lipophilicity and low water solubility of most
CB 1 and CB 2 receptor ligands as this necessitates
Receptor Agonist
the use of a non-aqueous vehicle such as ethanol,
dimethyl sulphoxide, polyvinylpyrrolidone, Tween 80,
Cat. No. 1343
Cremophor, Emulphor, bovine serum albumin
or the water-soluble emulsion Tocrisolve 100,
which is a mixture of soya oil, Pluronic F68 and
Me Me
water. 1,46,47 Consequently, one other cannabinoid
JWH 133 is a potent CB 2 agonist that displays approximately
CB 1 /CB 2 receptor agonist
200-fold selectivity over CB 1 receptors (K i values are 3.4 and
mention is the Organix compound, 3-(5´-cyano-
677 nM respectively). In vivo , JWH 133 reduces spasticity
in a murine autoimmune model of multiple sclerosis. The
8 -THC hydrochloride (O-1057), 48 as this is readily
superior selectivity, potency and in vivo activity of this CB 2
soluble in water. The in vitro potency of O-1057
agonist make it an important and essential tool for studying
relative to that of CP 55,940 is just 2.9 times less at
the physiological function of CB 2 receptors.
Huffman et al (1999) 3-(1´-Dimethylbutyl)-1-deoxy- 8 -THC and related
CB 1 receptors and 6.5 times less at CB 2 receptors.
compounds: synthesis of selective ligands for the CB 2 receptor. Bioorg.Med.
Chem. 7 2905. Pertwee (1999) Pharmacology of cannabinoid receptor ligands.
CB 1 -Selective Agonists
Curr.Med.Chem. 6 635. Baker et al (2000) Cannabinoids control spasticity and
For the development of the first CB 1 -selective
tremor in a multiple sclerosis model. Nature 404 84.
agonists, the starting point was the anandamide
(DEA controlled substance. Please consult your local
molecule, the marginal CB 1 selectivity of which can
office for further information. Canadian customers
require a CDSA import permit)
be significantly enhanced by inserting a fluorine atom
on the terminal 2´ carbon to form O-585 and/or by
mediated hydrolysis. 51 This structural change also
replacing a hydrogen atom on the 1´ or 2 carbon with
reduces the affinity of ACEA for CB 1 receptors by
a methyl group to form ( R )-(+)-Methanandamide
about 14-fold. One other arachidonic acid derivative
its cyano analogue O-1812, or O-689. 1,2,41 Another
that deserves mention as a CB 1 -selective agonist is
important consequence of inserting a methyl
2-arachidonylglyceryl ether (noladin ether), not least
group on the 1´ or 2 carbon is greater resistance
because it is a putative endocannabinoid. 52 This
to the hydrolytic action of FAAH and, indeed,
ligand exhibits CP 55,940-like CB 1 efficacy but less
CB 1 potency than CP 55,940. 53,54 The structures of
in Dr Alexandros Makriyannis’ laboratory in order
to meet the need for a metabolically more stable
noladin ether are shown in Figure 3 and the CB 1
anandamide analogue. Together with O-1812, 49 the
and CB 2 binding properties of these compounds are
most potent CB 1 -selective agonists so far developed
summarised in Table 2.
have been arachidonyl-2´-chloroethylamide (ACEA)
and arachidonylcyclopropylamide (ACPA), both of
CB 2 -Selective Agonists
which exhibit reasonably high CB 1 efficacy. 50 However,
The CB 2 -selective agonists most widely used
unlike O-1812, or indeed methanandamide or O-689,
as experimental tools have been the classical
neither ACEA nor ACPA show any sign of resistance to
cannabinoid, JWH 133, and the less selective
enzymic hydrolysis. 1,2,49 This is presumably because
aminoalkylindole, JWH 133, both developed by
they lack a methyl substituent on the 1´ or 2 carbon
Dr John Huffman. 1,2,72 Each of these agents not only
and, indeed, it has been shown that the addition of a
binds more readily to CB 2 than to CB 1 receptors
methyl group to the 1´ carbon of ACEA does markedly
but also behaves as a potent CB 2 -selective agonist
decrease the susceptibility of this molecule to FAAH-
in functional assays. Other notable CB 2 -selective
Figure 4 | Structures of the CB 2 -selective agonists JWH 133, JWH 015, HU 308, AM 1241 and
GW 405833 (see also Table 2)
NO 2
HU 308
AM 1241
(Bold Text Denotes Compounds Available From Tocris)
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