han the rat receptor as yet

undefined, mechanisms may be involved. The

in vivo efficacy of R,S AM1241

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its enantiomers was assessed in rodent

models of acute, inflammatory and visceral

pain. Neither R,S AM1241 nor either

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its enantiomers showed evidence of acute

nociception in either the tailflick or hot

plate assay. This is the first report of

the effects of the AM1241 enantiomers in

an assay of acute nociceptive pain. Our

results, although in contrast with an

earlier report demonstrating analgesic

effects of racemic AM1241, are consistent

with studies demonstrating that other CB2

agonists are not analgesic in vivo.
S

AM1241 was

href="http://www.selleckbio.com/bms-806-

S2632.html">buy BMS 378806 efficacious

in the mouse PPQ model, as was R

AM1241.
However, the latter compound

had only a modest antinociceptive effect,

and the racemate had no statistically

significant effect in this model. The lone

previous report of in vivo efficacy

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S2632.html">buy BMS 378806 of a

resolved stereoisomer of AM1241 was an

investigation of AM1241 in a mouse pain

model that used intraplantar formalin

injection. In light of our

characterization of the resolved

enantiomers, particularly the

antinociceptive effects of S AM1241, it

would be of interest to compare the

efficacy of both enantiomers in the

formalin induced pain model. In the rat

carrageenan model of inflammatory pain, S

AM1241, an agonist at rCB2 receptors, was

more efficacious than the racemate against

thermal hyperalgesia, whereas R AM1241, an

inverse agonist, lacked statistically

significant efficacy.

The

antihyperalgesic effect of S AM1241 was

blocked by the CB2 antagonist AM630,

demonstrating that the activity of S

AM1241 was mediated by CB2

receptors. Additional off

href=""> target effects of S AM1241

cannot be ruled out, but the magnitude of

the AM630 induced blockade should be

interpreted as evidence that any non CB2

components of this effect would be minor

in comparison to the CB2 component. Our

results in the carrageenan model are

consistent not only with previous reports

of antinociceptive efficacy following

administration of racemic AM1241, but also

with reports of efficacy achieved with

other CB2 agonists in models of

inflammatory pain.
Whereas the in vivo

efficacy of S AM1241 in rodent pain models

is consistent with the in vitro functional

characterization of this enantiomer as a

rodent CB2 agonist, the in vivo efficacy

of R,S AM1241 and R AM1241 in the same

rodent pain models appears to be

inconsistent with their in vitro

characterization as inverse agonists.

In the absence of constitutive CB2

receptor activity in vivo, the prediction

following from the protean agonist

hypothesis is that R AM1241 would behave

as a partial agonist. In that case, the

efficacy of R AM1241 in the mouse formalin

and PPQ models and the efficacy of the

racemate in multiple pain models would be

consistent with the in vitro

characterization of these compounds.

However, constitutive activation of

receptors is an elusive property to

measure in vivo. In one case in which this

property has been deduced for CB2

receptors, the in vivo efficacy of CB2

selective inverse agonists in the

inhibition of leucocyte trafficking

provides evidence of the existence of

constitutive CB2 receptor activity in

rodents. This condition, if it holds in

our rodent pain models, woul