Biology Reference
In-Depth Information
2.4 Therapeutic opportunity
Even though the detailed pathophysiology of the EC system is not yet fully understood,
there is already overwhelming evidence indicating that a pharmacological modulation of the
endogenous cannabinoid system could provide new tools for a number of disease states,
including drug addiction. Recent evidence suggests that the blockade of CB1 receptors with
SR141617A (Fig. 6) might be beneficial to alleviate motor inhibition typical of Parkinson's
disease (PD) [79]. In addition to SR, several specific EC transport inhibitors, FAAH and
MAGL inhibitors which regulate brain EC levels might have a therapeutic value in the
protection against Aβ-induced neurodegeneration [197]
and memory deficit in rodents [140].
Figure 6. Molecular structure of CB1 receptor-selective antagonist/inverse agonist, rimonabant.
SR141716A is a highly potent and selective CB1 receptor ligand that readily prevents and reverses CB1
mediated effects both in vitro and in vivo [98]
The CB1 receptor antagonist SR has progressed furthest and is in late phase III trials for
the treatment of obesity and as an aid for smoking cessation [48, 198]. An NIAAA clinical
study of the efficacy of SR to reduce voluntary alcohol drinking is in phase I trials.
Pending
the results of the clinical trials, SR could become an important addition to the limited arsenal
of effective treatments for alcoholism.
During disease or drug abuse, including alcohol
abuse[15], there are changes in EC levels in various regions of the brain [12, 18, 175, 208].
Therefore, drugs or agents which regulate the level of ECs by inhibiting their metabolism
(FAAH inhibitors such as URB597) or uptake (AM404) or synthesis (orlistat) could locally
target sites while limiting the effects on uninvolved cognitive areas, and would thus be
expected to have a higher therapeutic value [21, 87]. EC interactions with the dopamine
system have been offered as a possible mechanism for some of the therapeutic potential of
cannabinoid-based drugs in alcoholism.
