3. Umbruch 4.4..2005 - Online Pot

Cannabinoid targets for pain therapeutics 157
concentrations in in vitro assays) or specificity (often also acting on the CB 1R
or other hydrolases). More recently, efforts from Boger’s and Cravatt’s groups
have resulted in the development of ultra-potent (effective at low nanomolar
concentrations) inhibitors of FAAH [106–108]. Some of these compounds,
such as URB532, URB597 and BMS-1, also affected other hydrolases, whereas
OL-135 was highly selective for FAAH and lacked activity at cannabinoid
receptors [109]. OL-135 suppressed pain in rodents in a CB 1-dependent manner
concurrent with elevated levels of endocannabinoids [109]. These results
are encouraging for the development of a clinically effective agent for pain
based on selective inhibition of FAAH.
Development of inhibitors of cellular transport of endogenous
cannabinoids
Another approach for manipulating the endocannabinoid system is with
inhibitors of the putative transport mechanism for the endocannabinoid anandamide.
Blocking cellular transport would be expected to cause increased
anandamide levels to occur in the vicinity of cannabinoid receptors, a similar
consequence as that caused by inhibition of FAAH. Several transport
inhibitors have been synthesized, beginning with the compound AM-404
[110], followed by VDM11 [111], OMDM-1, OMDM-2 [112], UCM707
[113] and UCM719 [114]. These compounds provided good separation in
potencies for anandamide uptake (low micromolar range) versus FAAH inhibition,
but most also bind to CB 1Rs at doses similar to those required for inhibition
of anandamide uptake. The best separation of these effects was found
with UCM707 and OMDM-1, which offered a 5–6-fold separation in dose.
Following similar rationales as those for FAAH inhibitors, it is likely that further
development of inhibitors of the cellular transport mechanisms for endocannabinoids
may be fruitful for clinical pain relief.
Synergism between cannabinoid and opioid agonists
The first indication of the existence of synergistic (greater than additive)
pain-suppressive effects from co-administration of cannabinoid and opioid
agonists came from a study by Ghosh and Bhattacharya [115] when they found
that cannabis enhanced the analgesic effect of morphine in the rat. Further
study into this phenomenon, with major contributions from Welch’s group,
have provided information on the particular cannabinoid agonists, the dosages,
and the routes of administration required for the synergy to occur [41,
116–118]. An isobolographic analysis has been reported in rats, which plots
the theoretical ED 50 for the drug combinations codeine/∆ 9 -THC and morphine/∆
9 -THC [119]. These synergistic effects of cannabinoid and opioid agonists
appeared to be receptor-mediated. Moreover, not only do low or inactive