Antagonists

Of the antagonists that have been developed, the best characterized and most widely-employed is the CB1 receptor-selective ligand SR141716A (Fig. 13.2, Table 13.3), which was discovered as a result of drug library screening (Rinaldi-Carmona et al. 1994). The antagonist is effective both in vitro and in vivo and displays very little activity at other receptor classes. It is apparent, however, that at relatively high concentrations (>1 ^M), SR141716A is able to block gap junctions (Chaytor et al. 1999) and to inhibit vanilloid VR1 receptors (De Petrocellis et al. 2001), but whether these effects contribute to its overall pharmacological profile in vivo is unclear. AM281, a structurally-related compound, shows relatively high CB1 receptor affinity (Table 13.3), with greater aqueous solubility, and has been labelled with iodine-131 for use as a SPECT ligand invivo (Gifford etal. 1997b). AM630 (Ross etal. 1999), with reduced efficacy at CB1 receptors, and SR144528 (Rinaldi-Carmona et al. 1998a) show good selectivity as CB2-selective antagonists (Fig. 13.2, Table 13.3).

Table 13.2 Agonist affinity at cannabinoid receptors

Compound

CBi cannabinoid receptors

CB2 cannabinoid receptors

Selectivity

affinity (nM)

Source

affinity (nM)

Source

CB1: CB2

ACEA

1.4

Human receptor*§a

>2000

Rat spleen*a

<0.0007

ACPA

2.2

Human receptor*§a

700

Rat spleen*a

0.0031

Methanandamide

20

Rat brain*b

815

Mouse spleen*b

0.025

Anandamide

89

Human receptor*§c

371

Human receptor*§c

0.24

2AG

472

Human receptor (COS-7 cells)*d

1400

Human receptor (COS-7 cells)*d

0.34

CP55940

0.58

Human receptor*§c

0.69

Human receptor*§c

0.84

THC

41

Human receptor*§c

36

Human receptor*§c

1.1

Cannabidiol

4350

Rat receptor*§c

2860

Human receptor*§c

1.5

Cannabinol

1130

Human receptor (L cells)*e

301

Human receptor (AtT-20 cells)*e

3.8

WIN55212-2

1.9

Human receptor*§c

0.28

Human receptor*§c

6.8

JWH015

383

Human receptor*§c

13.8

Human receptor*§c

27.8

L759656

4900

Human receptor*§f

11.8

Human receptor*§f

415

HU308

>10000

Rat braintg

23

Rat receptort§g

>435

L759633

1000

Human receptor*§e

0.4

Human receptor*§e

2500

* Competition for [3H]-CP55,940 binding; t Competition for [3H]-HU243 binding; ^Expressed in Chinese Hamster ovary cells; a(Hillard etal. 1999); b(Khanolkar etal. 1996); c(Showalter etal. 1996); d(Mechoulam etal. 1995); e(Felderetal. 1995);f(Rossetal. 1999); g(Hanusetal. 1999). Key: 2AG: 2-arachidonoylglycerol; ACEA: arachidonoyl-2-chloroethylamide; ACPA arachidonoyl-cyclopropylamide; CP55940:

(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol; JWH133: 3-(1',1'-dimethylbutyl)-1-deoxy-A8-tetrahydrocannabinol; L759633:

(6aR,10aR)-3-(1,1-dimethylheptyl)-1-methoxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene; L759656: (6aR,10aR)-3-(1,1-dimethylheptyl)-1-methoxy-6,6-dimethyl-9-methylene-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene; methanandamide: (fl)-(+)-arachidonoyM'-hydroxy-2'-propylamide; THC: A9-tetrahydrocannabinol; WIN5521 2-2: (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone.

There are reports of SR141716A having CBi receptor inverse agonist properties in cell lines, peripheral organs and brain (Landsman et al. 1997; MacLennan et al. 1998; Pan et al. 1998; Meschler et al. 2000). Other less well characterized CB1 receptor ligands also appear to exhibit inverse agonist properties (Landsman et al. 1998; Meschler et al. 2000). Recent studies measuring [35S]-GTPyS binding in brain sections, however, indicate that SR141716 is a competitive antagonist in the nanomolar concentration range but an inverse agonist at micromolar levels (Sim-Selley etal. 2001). Furthermore, it appears that the apparent inverse

Table 13.3 Antagonist affinity at cannabinoid receptors

Compound

CBi cannabinoid receptors

CB2 cannabinoid receptors

Selectivity

affinity (nM)

Source

affinity (nM)

Source

CB1 : CB2

LY32013 5

224

Human receptor*§a

>10000

Human receptor*§a

<0.022

SR141716A

11 2 2

Human receptor*§b Rat brain*c

Mouse vas deferens§d

702

Human receptor*§b

0.016

AM630

5152

Human receptor*§e

31

Human receptor*§e

166

SR144528

305 437

Rat brain*f Human receptor*§f

0.3 0.6

Rat spleen*f Human receptor*§f

508 728

AM281

14

Rat hippocampus*9

* Competition for [3H]-CP55940 binding; t Competition for [3H]-HU243 binding; ^Expressed in Chinese hamster ovary cells; 'Antagonism of the cannabinoid inhibition of electrically-evoked contractions; a(Felder et al. 1998); b(Showalter et al. 1996); c(Rinaldi-Carmona etal. 1994); d(Petwee etal. 1995); e(Ross etal. 1999); f(Rinaldi-Carmona etal. 1998); g(Gifford etal. 1997)

* Competition for [3H]-CP55940 binding; t Competition for [3H]-HU243 binding; ^Expressed in Chinese hamster ovary cells; 'Antagonism of the cannabinoid inhibition of electrically-evoked contractions; a(Felder et al. 1998); b(Showalter et al. 1996); c(Rinaldi-Carmona etal. 1994); d(Petwee etal. 1995); e(Ross etal. 1999); f(Rinaldi-Carmona etal. 1998); g(Gifford etal. 1997)

Key: AM281 W-(morpholin-4-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; AM630: 6-iodopravadoline; LY320135:

[6-methoxy-2-(4-methoxyphenyl)benzo[b]thien-3-yl][4-cyanophenyl]methanone;

SR141716A: W-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3carboxamide hydrochloride; SR144528: W-([1S]-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide.

agonist effect is either not cannabinoid CB1 receptor-specific or that different sites on the cannabinoid CB1 receptor mediate antagonist and inverse agonist effects.

SR144528 and JTE-907, a novel selective ligand for CB2 cannabinoid receptors, have also been reported to have inverse agonist properties at human overexpressed CB2 receptors (Shire etal. 1999; Iwamura etal. 2001).

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