(R)-AM-1241 is enantiomer of the CB2 modulator, that has most penetrated the literature, has proven an important research tool for investigating CB2-mediated antinociception. (R, S)-AM1241 produces antinociception following local and systemic administration in naive rats. Behavioral, neurochemical, and electrophysiological studies suggest that (R, S)-AM1241 suppresses persistent pain through a CB2-specific mechanism. In cAMP inhibition assays, (R, S)-AM1241 was found to be an agonist at human CB(2), but an inverse agonist in 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. In preclinical studies (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 produced antinociception to thermal, but not mechanical, stimulation of the hind paw 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. (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 each produced CB2-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 physiological and toxicological properties of (R)-AM-1241 have not been evaluated in humans.