AM1241

IC50: AM-1241 is a selective cannabinoid CB2 receptor agonist with Ki of 3.4 nM, exhibits 82-fold selectivity over CB1 receptor. [1].
The cannabinoid receptor type 2, abbreviated as CB2, is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as Alzheimer's disease. AM-1241, a chemical from the aminoalkylindole family, acts as a potent and selective agonist for the cannabinoid receptor CB2, has analgesic effects in animal studies, particularly against "atypical" pain such as hyperalgesia and allodynia.
In vitro: The purpose of our studies was to provide a characterization of R,S-AM1241 and its resolved enantiomers in vitro and in vivo. In cAMP inhibition assays, R,S-AM1241 was found to be an agonist at human CB2, but an inverse agonist at rat and mouse CB2 receptors. R-AM1241 bound with more than 40-fold higher affinity than S-AM1241, to all three CB2 receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB2 receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. Antagonist blockade demonstrated that the in vivo effects of S-AM1241 were mediated by CB2 receptors. These findings constitute the first in vitro functional assessment of R,S-AM1241 at rodent CB2 receptors and the first characterization of the AM1241 enantiomers in recombinant cell systems and in vivo. The greater antinociceptive efficacy of S-AM1241, the functional CB2 agonist enantiomer of AM1241, is consistent with previous observations that CB2 agonists are effective in relief of pain [2].
In vivo:
Effective treatment or amyotrophic lateral sclerosis (ALS) remains elusive. Motor neuron degeneration is the primary pathology in ALS; however non-neuronal cells contribute to the disease process. In particular, inflammatory processes have been shown to play an important role. AM1241 is a cannabinoid CB2 receptor selective agonist that has been shown to be effective in models of inflammation and hyperalgesia. Here we report that treatment with AM1241 was effective at slowing signs of disease progression when administered after onset of signs in an ALS mouse model (hSOD1G93A transgenic mice). Administration at the onset of tremors delayed motor impairment in treated mice when compared to vehicle controls. Three conditions of ALS, the loss of motor function, paralysis scoring and weight loss, were analyzed using a mathematical model. Loss of motor function (as assessed by performance on a rotarod) was delayed by 12.5 days in male mice by AM1241. In female mice, AM1241 extended rotarod performance by 3 days, although this was not statistically significant. In male mice, AM1241 also extended by 5 days the time to reach the 50%point on a visually-assessed performance scale.AM1241 did not affectweight loss or survival (129.8±1.7 days, vehicle; 129.1±7.0 days, AM1241, n=16). As AM1241 was well tolerated by the animals, cannabinoid CB2 receptor-selective compounds may be the basis for developing new drugs for the treatment of ALS and other chronic neurodegenerative diseases [3].
Clinical trial: AM1241 is still in preclinical development phase and no clinical study has been found.
Reference:
[1] Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, Vanderah TW, Lai J, Porreca F, Makriyannis A, Malan TP Jr. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A. 2003;100(18):10529-33.
[2] B Bingham, PG Jones, AJ Uveges, S Kotnis, P Lu, VA Smith, S-C Sun, L Resnick, M Chlenov, Y He. Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers. British Journal of Pharmacology (2007) 151, 1061–1070
[3] Kathline Kim, Dan H. Moore, Alexandros Makriyannis, Mary E. Abood. AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. European Journal of Pharmacology 542 (2006) 100-105