Cannabinoid Receptor Ligands
are in fact inverse agonists. 74 More specifically, they
appear to produce inverse cannabimimetic effects
LY 320135, CB 1 Antagonist/
in at least some tissues by somehow reducing the
constitutive activity of CB 1 receptors (the coupling of
Inverse Agonist
CN
CB 1 receptors to their effector mechanisms that, it is
O
thought, can occur in the absence of exogenously
Cat. No. 2387
added or endogenously released CB 1 agonists).
OMe
The structures of SR141716A, AM 251, AM 281
MeO
O
and LY 320135 are shown in Figure 5 and the CB 1
and CB 2 binding properties of these compounds are
LY 320135 is a CB 1 receptor antagonist that is structurally
summarised in Table 2.
dissimilar from SR 141716A and AM 251. The compound
produces inverse agonist effects and displays > 70-fold
Selective CB 2 Receptor Antagonists/
selectivity for CB 1 over CB 2 receptors (K i values are 141 nM
Inverse Agonists
and > 10 µ M respectively. It shows weak binding to both
5-HT 2 (K i = 6.4 µ M) and muscarinic receptors (K i = 2.1 µ M).
The most notable CB 2 -selective antagonists/inverse
Felder et al (1998) LY320135, a novel cannabinoid CB 1 receptor antagonist,
agonists are the Sanofi-Aventis diarylpyrazole,
unmasks coupling of the CB 1 receptor to stimulation of cAMP accumulation.
SR144528, 69 and 6-iodopravadoline (AM 630) 71
J.Pharmacol.Exp.Ther. 284 291. Holland et al (1999) Cannabinoid CB 1
receptors fail to cause relaxation, but couple via G i /G o to the inhibition of
(Figure 5). Both compounds bind with much higher
adenylyl cyclase in carotid artery smooth muscle. Br.J.Pharmacol. 128 597.
affinity to CB 2 than to CB 1 receptors (Table 2), exhibit
Pertwee (2005) Inverse agonism and neutral antagonism at cannabinoid CB 1
marked potency as CB 2 receptor antagonists and
receptors. Life Sci. 76 1307.
behave as inverse agonists that can by themselves
produce inverse cannabimimetic effects at CB 2
Figure 5 | Structures of the CB 1 -selective
receptors. 1,2,41 Thus for example, AM 630 has been
antagonists/inverse agonists, SR141716A,
reported to reverse CP 55,940-induced inhibition
AM 251, AM 281 and LY 320135, and of the
of forskolin-stimulated cyclic AMP production by
CB 2 -selective antagonists/inverse agonists,
human CB 2 -transfected CHO cell preparations
SR144528 and AM 630 (see also Table 2)
at
concentrations
in
the
nanomolar
range
(EC 50 = 129 nM) and to enhance forskolin-stimulated
cyclic AMP production by the same cell line when
O
N
O
N
administered by itself (EC 50 = 230 nM), 71 albeit with
NH
NH
an efficacy that appears to be somewhat less than
N
N
the inverse efficacy displayed by SR144528 in this
N
N
Cl
Cl
bioassay. 75 At the CB 1 receptor, AM 630 has been
Cl
I
found to behave in some investigations as a low-
potency partial agonist 41,71,76-78 but in others as a low-
Cl
Cl
potency inverse agonist. 79,80
SR141716A
O
AM 251, Potent CB 1 -Selective
O
N
Antagonist/Inverse Agonist
NH
CN
N
O
O
N
N
Cat. No. 1117
Me
NH
Cl
I
OMe
N
MeO
O
N
Cl
Cl
I
Cl
AM 251 is a potent and selective CB 1 receptor antagonist/
O
inverse agonist. Structurally related to SR141716A, AM 251
O
displays a K i value of 7.49 nM at CB 1 receptors and is 306-
NH
fold selective over CB 2 receptors. It suppresses food intake
I
N
OMe
and food-reinforced behaviour in rats.
N
N
Gatley et al (1996) 125 I-labeled AM 251: a radioiodinated ligand which binds
N
in vivo to mouse brain cannabinoid CB 1 receptors. Eur.J.Pharmacol. 307 331.
Cl
Gatley et al (1997) Binding of the non-classical cannabinoid CP 55,940, and the
O
diarylpyrazole AM251 to rodent brain cannabinoid receptors. Life Sci. 61 191.
Pertwee (2005) Inverse agonism and neutral antagonism at cannabinoid CB 1
receptors. Life Sci. 76 1307.
SR144528
(Sold with the permission of the University of Connecticut)
(Bold Text Denotes Compounds Available From Tocris)
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