AM630

AM630 is a selective and competitive antagonist of cannabinoid receptors with Ki values of 5 μM and 31.2 nM for CB1 receptor and CB2 receptor, respectively [1].

In CB1-transfected CHO cells, AM630 significantly inhibited the production of cAMP stumilated by forskolin. In CB2-transfected cells, AM630 promoted forskolin to stimulate cyclic AMP production with EC50 value of 230.4 nM. AM630 also exerted to have inhibitory effect on the binding of GTPγS to membranes from CB2-transfected cells. Besides that, AM630 was found to activate the TRPA1 channels and subsequently desensitizing TRPA1 and TRPV1 channels in TG sensory neurons. Moreover, AM630 significantly weakened the thermal hyperalgesia induced by CAP (capsaicin) in WT mice [1, 2].

References:
1. Ross R A, Brockie H C, Stevenson L A, et al. Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and AM630. British journal of pharmacology, 1999, 126(3): 665-672.
2. Patil M, Patwardhan A, Salas M M, et al. Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons. Neuropharmacology, 2011, 61(4): 778-788.

Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons.[Pubmed:21645531]

Neuropharmacology. 2011 Sep;61(4):778-88.

Cannabinoid receptor antagonists have been utilized extensively in vivo as well as in vitro, but their selectivity has not been fully examined. We investigated activation of sensory neurons by two cannabinoid antagonists - AM251 and AM630. AM251 and AM630 activated trigeminal (TG) sensory neurons in a concentration-dependent fashion (threshold 1 muM). AM251 and AM630 responses are mediated by the TRPA1 channel in a majority (90-95%) of small-to-medium TG sensory neurons. AM630 (1-100 muM), but not AM251, was a significantly more potent agonist in cells co-expressing both TRPA1 and TRPV1 channels. We next evaluated AM630 and AM251 effects on TRPV1- and TRPA1-mediated responses in TG neurons. Capsaicin (CAP) effects were inhibited by pre-treatment with AM630, but not AM251. Mustard oil (MO) and WIN55,212-2 (WIN) TRPA1 mediated responses were also inhibited by pre-treatment with AM630, but not AM251 (25 uM each). Co-treatment of neurons with WIN and either AM630 or AM251 had opposite effects: AM630 sensitized WIN responses, whereas AM251 inhibited WIN responses. WIN-induced inhibition of CAP responses in sensory neurons was reversed by AM630 pre-treatment and AM251 co-treatment (25 muM each), as these conditions inhibit WIN responses. Hindpaw injections of AM630 and AM251 did not produce nocifensive behaviors. However, both compounds modulated CAP-induced thermal hyperalgesia in wild-type mice and rats, but not TRPA1 null-mutant mice. AMs also partially regulate WIN inhibition of CAP-induced thermal hyperalgesia in a TRPA1-dependent fashion. In summary, these findings demonstrate alternative targets for the cannabinoid antagonists, AM251 and AM630, in peripheral antihyperalgesia which involve certain TRP channels.

AM630 behaves as a protean ligand at the human cannabinoid CB2 receptor.[Pubmed:21615724]

Br J Pharmacol. 2012 Apr;165(8):2561-74.

BACKGROUND AND PURPOSE: We have investigated how pre-incubating hCB(2) CHO cells with the CB(2) receptor antagonists/inverse agonists, AM630 and SR144528, affects how these and other ligands target hCB(2) receptors in these cells or their membranes. EXPERIMENTAL APPROACH: We tested the ability of AM630, SR144528 and of the CB(1) /CB(2) receptor agonists, CP55940 and R-(+)-WIN55212, to modulate forskolin-stimulated cAMP production in hCB(2) CHO cells or [(35) S]-GTPgammaS binding to membranes prepared from these cells, or to displace [(3) H]-CP55940 from whole cells and membranes. Assays were also performed with the CB(2) receptor partial agonist, Delta(9) -tetrahydrocannabivarin. Some cells were pre-incubated with AM630 or SR144528 and then washed extensively. KEY RESULTS: AM630 behaved as a low-potency neutral competitive antagonist in AM630-pre-incubated cells, a low-potency agonist in SR144528-pre-incubated cells, and a much higher-potency inverse agonist/antagonist in vehicle-pre-incubated cells. AM630 pre-incubation (i) reduced the inverse efficacy of SR144528 without abolishing it; (ii) increased the efficacy of Delta(9) -tetrahydrocannabivarin; and (iii) did not affect the potency with which AM630 displaced [(3) H]-CP55940 from whole cells or its inverse agonist potency and efficacy in the [(35) S]-GTPgammaS membrane assay. CONCLUSIONS AND IMPLICATIONS: These results suggest that AM630 is a protean ligand that can target a constitutively active form of the hCB(2) receptor (R*) with low affinity to produce agonism or neutral antagonism and a constitutively inactive form of this receptor (R) with much higher affinity to produce inverse agonism, and that the constitutive activity of whole cells is decreased less by pre-incubation with AM630 than with the higher-efficacy inverse agonist, SR144528. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Inhibition of titanium particle-induced inflammatory osteolysis through inactivation of cannabinoid receptor 2 by AM630.[Pubmed:20623669]

J Biomed Mater Res A. 2010 Oct;95(1):321-6.

Wear particle could induce inflammatory osteolysis and is the primary pathological factor for aseptic loosening. Although it is known that cannabinoid receptor 2 (CB2) inhibits osteoclast differentiation, the effect on inflammatory osteolysis induced by wear particles remains unclear. This study examined the effect of CB2 in the regulation of osteoclast differentiation in a murine macrophage cell line (RAW264.7), which has been shown to be stimulated by titanium (Ti) particles and receptor activator of the NF-kappaB ligand (RANKL). Results showed that CB2 expression in RAW cells cultured with Ti particles and RANKL. CB2 inactivation by AM630, a CB2 selective antagonist, effectively inhibited osteoclastogenesis in the differentiation medium system. AM630 treatment (> or =100 nM) significantly reduced the number of tartrate-resistant acid phosphatase-positive cells when compared with the control. Real-time reverse transcription polymerase chain reaction analysis revealed that AM630 (100 nM) inhibited mRNA expression of RANK and cathepsin K in RAW cells stimulated by Ti particles and RANKL. Moreover, enzyme-linked immunosorbent assay showed that AM630 (100 nM) reduced protein expression of interleukin-1beta and tumor necrosis factor-alpha in RAW cells cultured with Ti particles. In addition, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide revealed that AM630 had no toxic effect on RAW cells. These results suggested that CB2 inactivation by AM630 could provide a promising therapeutic target for treating or preventing aseptic loosening.

Effects of the cannabinoid antagonists AM281 and AM630 on deprivation-induced intake in Lewis rats.[Pubmed:12650991]

Brain Res. 2003 Mar 28;967(1-2):290-2.

Male Lewis rats (two groups of 10) received intracerebroventricular injections of either AM 630 (vehicle, 2.5, 5, 10 and 20 microg) or AM 281 (vehicle, 5, 10, 20 and 40 microg) following overnight food deprivation. The CB2 antagonist AM 630 failed to block deprivation-induced intake at 0.5, 1, 2, 4 and 6 h. The CB1 antagonist AM 281 significantly blocked intake following 20 microg (1 h) and 40 microg (1, 2, 4 and 6 h). Results are discussed with respect to cannabinoid receptor systems' involvement in ingestion and the differential pharmacological profiles of AM 630 and AM 281.

Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630.[Pubmed:10188977]

Br J Pharmacol. 1999 Feb;126(3):665-72.

We have tested our prediction that AM630 is a CB2 cannabinoid receptor ligand and also investigated whether L759633 and L759656, are CB2 receptor agonists. Binding assays with membranes from CHO cells stably transfected with human CB1 or CB2 receptors using [3H]-CP55940, confirmed the CB2-selectivity of L759633 and L759656 (CB2/CB1 affinity ratios = 163 and 414 respectively) and showed AM630 to have a Ki at CB2 receptors of 31.2 nM and a CB2/CB1 affinity ratio of 165. In CB2-transfected cells, L759633 and L759656 were potent inhibitors of forskolin-stimulated cyclic AMP production, with EC50 values of 8.1 and 3.1 nM respectively and CB1/CB2 EC50 ratios of > 1000 and > 3000 respectively. AM630 inhibited [35S]-GTPgammaS binding to CB2 receptor membranes (EC50 = 76.6 nM), enhanced forskolin-stimulated cyclic AMP production in CB2-transfected cells (5.2 fold by 1 microM), and antagonized the inhibition of forskolin-stimulated cyclic AMP production in this cell line induced by CP55940. In CB1-transfected cells, forskolin-stimulated cyclic AMP production was significantly inhibited by AM630 (22.6% at 1 microM and 45.9% at 10 microM) and by L759633 at 10 microM (48%) but not 1 microM. L759656 (10 microM) was not inhibitory. AM630 also produced a slight decrease in the mean inhibitory effect of CP55940 on cyclic AMP production which was not statistically significant. We conclude that AM630 is a CB2-selective ligand that behaves as an inverse agonist at CB2 receptors and as a weak partial agonist at CB1 receptors. L759633 and L759656 are both potent CB2-selective agonists.

AM630 is an inverse agonist at the human cannabinoid CB1 receptor.[Pubmed:9496703]

Life Sci. 1998;62(9):PL109-13.

The present investigation examines WIN 55,212-2 and AM630 at the cloned human cannabinoid CB1 receptor stably expressed in Chinese hamster ovary (CHO) cells. The effect of various concentrations of WIN 55,212-2 and AM630 on basal [35S]GTPgammaS binding to cell membranes was determined. WIN 55,212-2 (100 microM) stimulated basal [35S]GTPgammaS binding 77.9% with an EC50 value of 0.36 microM. Conversely, AM630 (100 microM) inhibited basal [35S]GTPgammaS binding by 20.9% with an EC50 value of 0.90 microM. These results show that WIN 55,212-2 is an agonist and AM630 is an inverse agonist in this system.

AM630 is a competitive cannabinoid receptor antagonist in the guinea pig brain.[Pubmed:9284087]

Life Sci. 1997;61(9):PL115-8.

AM630 has been demonstrated to be a cannabinoid receptor antagonist in the mouse brain and vas deferens. Conversely, it was recently reported that AM630 acts as a cannabinoid agonist in the guinea pig ileum. This research was designed to determine whether the difference in the action of AM630 is species specific. Studies conducted in guinea pig brain reveal that AM630 antagonizes the stimulatory effect of the cannabinoid agonist WIN 55,212-2 on [35S]GTPgammaS binding suggesting that difference in AM630 activity in different tissues is not due to species variation.

AM630 antagonism of cannabinoid-stimulated [35S]GTP gamma S binding in the mouse brain.[Pubmed:9083796]

Eur J Pharmacol. 1997 Feb 19;321(1):R1-3.

This research was designed to determine the action of the novel aminoalkylindole AM630 (6-iodo-pravadoline) at the cannabinoid receptor by studying its interaction with the cannabinoid receptor agonist WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-y]-(1-naphthalenyl)methanone mesylate) on guanosine-5'-O-(3-[35S]thio) triphosphate ([35S]GTP gamma S) binding in mouse brain. WIN 55,212-2 stimulated [35S]GTP gamma S binding, while AM630 had no effect. AM630 antagonized WIN 55,212-2-2induced [35S]GTP gamma S binding and shifted the WIN 55,212-dose-response curve to the right. These results clearly demonstrate that AM630 exerts cannabinoid receptor antagonist properties in the brain.

6-Iodopravadoline (AM630) is a selective CB2 antagonist with Ki of 31.2 nM, and displays 165-fold selectivity over CB1 receptors.

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