(S)-AM1241
(Synonyms: (-)AM1241) 目录号 : GC40595A CB2 receptor agonist
Cas No.:444912-53-2
Sample solution is provided at 25 µL, 10mM.
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(S)-AM1241 binds to cannabinoid (CB) receptors and is selective for the CB2 over the CB1 receptor (Kis = 658 and >10,000 nM, respectively, in a membrane assay using human receptors). (S)-1241 acts as an agonist at human, rat, and mouse CB2 receptors but shows greater activity at human CB2 (EC50 = 131 nM) than at rat and mouse CB2 receptors (EC50 = 785 and 2,000 nM, respectively). Similar to the racemate AM1241 , (S)-AM1241 produces antinociception to thermal, but not mechanical, pain in rats. The pain-reducing effect of (S)-AM1241 is blocked by the CB2-specific inhibitor SR 144528 but not by either the CB1-selective inhibitor rimonabant or the opioid receptor blocker naloxone .
Cas No. | 444912-53-2 | SDF | |
别名 | (-)AM1241 | ||
Canonical SMILES | O=C(C1=CC([N+]([O-])=O)=CC=C1I)C2=CN(C[C@@H]3CCCCN3C)C4=CC=CC=C42 | ||
分子式 | C22H22IN3O3 | 分子量 | 503.3 |
溶解度 | DMF: 25 mg/ml,DMF:PBS(pH7.2) (1:2): 0.3 mg/ml,DMSO: 10 mg/ml,Ethanol: 5 mg/ml | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.9869 mL | 9.9344 mL | 19.8689 mL |
5 mM | 0.3974 mL | 1.9869 mL | 3.9738 mL |
10 mM | 0.1987 mL | 0.9934 mL | 1.9869 mL |
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Antinociceptive effects of racemic AM1241 and its chirally synthesized enantiomers: lack of dependence upon opioid receptor activation
AAPS J 2010 Jun;12(2):147-57.PMID:20127295DOI:10.1208/s12248-009-9170-8.
Cannabinoid CB(2) receptors represent a therapeutic target that circumvents unwanted central side effects (e.g., psychoactivity and/or addiction) associated with activation of CB(1) receptors. One of the primary investigative tools used to study functions of the CB(2) receptor is the aminoalkylindole (R,S)-AM1241. However, (R,S)-AM1241 has been described as an atypical CB(2) agonist which produces antinociception mediated indirectly by opioid receptors. (R,S)-AM1241 and its enantiomers, (R)-AM1241 and (S)-AM1241, were evaluated for antinociception in response to thermal (Hargreaves) and mechanical (von Frey) stimulation. Pharmacological specificity was established using antagonists for CB(1) (rimonabant [SR141716]) and CB(2) (SR144528). The opioid antagonist naloxone was administered locally in the paw or systemically to evaluate the contribution of opioid receptors to CB(2)-mediated antinociception produced by (R,S)-AM1241, (R)-AM1241, and (S)-AM1241. Comparisons were made with the opioid analgesic morphine. (R,S)-AM1241, (R)-AM1241, and (S)-AM1241 (0.033-10 mg/kg i.p.) produced antinociception to thermal, but not mechanical, stimulation of the hindpaw in naive rats. Antinociception produced by (R,S)-AM1241 and (S)-AM1241 exhibited an inverted U-shaped dose response curve. (R)-AM1241 produced greater antinociception than either (S)-AM1241 or (R,S)-AM1241 at the lowest (0.033 and 0.1 mg/kg i.p.) and highest (10 mg/kg i.p.) doses. Similar levels of antinociception were observed at intermediate doses. (R,S)-AM1241, (R)-AM1241, and (S)-AM1241 each produced CB(2)-mediated antinociception that was blocked by SR144528 but not by rimonabant. Local and systemic naloxone blocked morphine-induced antinociception but did not block antinociceptive effects of (R,S)-AM1241, (R)-AM1241, or (S)-AM1241. The antinociceptive effects of the CB(2)-selective cannabinoid (R,S)-AM1241 and its enantiomers, (R)-AM1241 and (S)-AM1241, are not dependent upon opioid receptors.
Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers
Br J Pharmacol 2007 Aug;151(7):1061-70.PMID:17549048DOI:10.1038/sj.bjp.0707303.
Background and purpose: Racemic (R,S) AM1241 is a cannabinoid receptor 2 (CB(2))-selective aminoalkylindole with antinociceptive efficacy in animal pain models. The purpose of our studies was to provide a characterization of R,S-AM1241 and its resolved enantiomers in vitro and in vivo. Experimental approach: Competition binding assays were performed using membranes from cell lines expressing recombinant human, rat, and mouse CB(2) receptors. Inhibition of cAMP was assayed using intact CB(2)-expressing cells. A mouse model of visceral pain (para-phenylquinone, PPQ) and a rat model of acute inflammatory pain (carrageenan) were employed to characterize the compounds in vivo. Key results: In cAMP inhibition assays, R,S-AM1241 was found to be an agonist at human CB(2), but an inverse agonist at rat and mouse CB(2) receptors. R-AM1241 bound with more than 40-fold higher affinity than S-AM1241, to all three CB(2) receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB(2) 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 CB(2) receptors. Conclusions and implications: These findings constitute the first in vitro functional assessment of R,S-AM1241 at rodent CB(2) 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 CB(2) agonist enantiomer of AM1241, is consistent with previous observations that CB(2) agonists are effective in relief of pain.
Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain
Pain 2011 Sep;152(9):1976-1987.PMID:21550725DOI:10.1016/j.pain.2011.03.038.
Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB(2) agonist to attenuate a neuropathic pain state. Self-medication of the CB(2) agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal thresholds in sham-operated or naive animals. The percentage of active lever responding was similar in naive groups self-administering vehicle or (R,S)-AM1241. The CB(2) antagonist SR144528 blocked both antiallodynic effects of (R,S)-AM1241 self-medication and the percentage of active lever responding in neuropathic (but not naive) rats. Neuropathic and sham groups exhibited similar percentages of active lever responding for (R,S)-AM1241 on a fixed ratio 1 (FR1) schedule. However, neuropathic animals worked harder than shams to obtain (R,S)-AM1241 when the schedule of reinforcement was increased (to FR6). (R,S)-AM1241 self-medication on FR1, FR3, or FR6 schedules attenuated nerve injury-induced mechanical allodynia. (R,S)-AM1241 (900μg intravenously) failed to produce motor ataxia observed after administration of the mixed CB(1)/CB(2) agonist WIN55,212-2 (0.5mg/kg intravenously). Our results suggest that cannabinoid CB(2) agonists may be exploited to treat neuropathic pain with limited drug abuse liability and central nervous system side effects. These studies validate the use of drug self-administration methods for identifying nonpsychotropic analgesics possessing limited abuse potential. These methods offer potential to elucidate novel analgesics that suppress spontaneous neuropathic pain that is not measured by traditional assessments of evoked pain.
Interaction of a Cannabinoid-2 Agonist With Tramadol on Nociceptive Thresholds and Immune Responses in a Rat Model of Incisional Pain
Am J Ther 2016 Nov/Dec;23(6):e1484-e1492.PMID:25370921DOI:10.1097/MJT.0000000000000131.
The aim of this study was to elucidate the antinociceptive interaction between cannabinoids and tramadol and their impact on proinflammatory response, in terms of serum intereleukin-6 (IL-6) and interleukin-2 (IL-2) release, in a rat model of incisional pain. Prospective randomized trial assessing the individual or combined application of intraperitoneal tramadol (10 mg/kg) and the selective cannabinoid-2 (CB-2) agonist (R,S)-AM1241 (1 mg/kg) applied postsurgical stress stimulus. Pharmacological specificity was established by antagonizing tramadol with naloxone (0.3 mg/kg) and (R,S)-AM1241 with SR144528 (1 mg/kg). Thermal allodynia was assessed by hot plate test 30 (T30), 60 (T60), and 120 (T120) minutes after incision. Blood samples for plasma IL-6 and IL-2 level determination were obtained 2 hours after incision. Data from 42 rats were included in the final analyses. Significant augmentation of thermal threshold was observed at all time points, after administration of either tramadol or (R,S)-AM1241 compared with the control group (P = 0.004 and P = 0.015, respectively). The combination of (R,S)-AM1241 plus tramadol promoted the induced antinociception in an important manner compared with control (P = 0.002) and (R,S)-AM1241 (P = 0.022) groups. Although the antiallodynic effect produced by tramadol was partially reversed by naloxone 30 and 60 minutes after incision (P = 0.028 and P = 0.016, respectively), SR144528 blocked the effects of (R,S)-AM1241 administration in a significant manner (P = 0.001) at all time points. Similarly, naloxone plus SR144528 also blocked the effects of the combination of (R,S)-AM1241 with tramadol at all time points (P = 0.000). IL-6 level in (R,S)-AM1241 plus tramadol group was significantly attenuated compared with control group (P = 0.000). Nevertheless, IL-2 levels remained unchanged in all experimental groups. It seems that the concomitant administration of a selective CB-2 agonist with tramadol in incisional pain model may improve antinociceptive effects and immune responses of cannabinoids, but this effect does not seem to be superior to that of tramadol alone.
Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats
J Pharmacol Exp Ther 2008 Nov;327(2):584-91.PMID:18664590DOI:10.1124/jpet.108.141994.
Activation of cannabinoid CB(2) receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB(2) receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the antitumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p./day) on 4 alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the Cremophor EL/ethanol/saline vehicle at the same times. Two structurally distinct cannabinoid CB(2) agonists, the aminoalkylindole (R,S)-AM1241 [(R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone] and the cannabilactone AM1714 (1,9-dihydroxy-3-(1',1'-dimethylheptyl)-6H-benzo[c]chromene-6-one), produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia after systemic administration. Pretreatment with the CB(2) antagonist SR144528 [5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide], but not the CB(1) antagonist SR141716 [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide], blocked the antiallodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or preinjection thresholds, consistent with mediation by CB(2). Administration of either the CB(1) or CB(2) antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the Cremophor EL vehicle in lieu of paclitaxel, whereas AM1714 induced a modest antinociceptive effect. Our data suggest that cannabinoid CB(2) receptors may be important therapeutic targets for the treatment of chemotherapy-evoked neuropathy.