CB1 receptors

Rimonabant is the first-in class CB1 receptor antagonist, which has recently reached the market in Europe (approval in the US is pending). The reduction of... 

Rimonabant is a selective CB1 receptor antagonist that is currently under investigation in phase III trials. CB1 receptors are found in the brain, adipose tissue, the GI tract, pituitary and adrenal glands, sympathetic ganglia, heart, lungs, liver, and bladder.17,18 Food cravings are diminished following inhibition of this receptor.19... 

Hilairet S, Bouaboula M, Carriere D, Le Fur G, Casellas P. Hypersensitization of the orexin 1 receptor by the CB1 receptor evidence for cross-talk blocked by the specific CB1 antagonist, SR141716. J Biol Chem 2003 278 23731-23737. 

The primary system of cannabimimetic activity is the nervous system. The CB1 receptor is omnipresent in the brain, especially in areas that control functions affected by cannabimimetics. One of the functions most pronouncedly influenced by cannabimimetics is motor behavior. Catalepsy, immobility, ataxia, and impairment of complex behavioral acts after acute administration of high doses of cannabimimetics are manifestations of such motor effects (Pertwee, 1997). In lower doses cannabimimetics produce the opposite effects. The very dense presence of CB1 in the cerebellum and the basal ganglia, areas responsible for motor activity, is... 

Furthermore, the presence of CB1 in the structures and pathways associated with the pathophysiology of Tourette s syndrome, and especially the functional link between CB1 and Di, D2, also argues that the endocannabinoid system may have some involvement in this disorder as well (Consroe, 1998). In addition, it has been suggested that activation of CB1 receptors, also owing to their link with the dopaminergic system, may reduce dyskinesia produced by L-DOPA in patients with Parkinson s disease (Brotsie, 1998). 

The CB1 receptors present in the hippocampus, amygdala, and cerebral cortex may be responsible for observations that cannabimimetics are effective against some types of seizures (Consroe, 1998). The anticonvulsant and antispastic effects of cannabinoids are well documented, however the mechanisms of these effects are still unclear (Nahas, 1999). 

Arnone M, Maruani J, Chaperon F. Selective inhibition of sucrose nd ethanol intake by SR141716a, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology 1998 132 104-106. 

Bramblett RD, Pann AM, Ballesteros JA, Reggio PH. Construction of 3D model of the cannabinoid CB1 receptor determination of helix ends and helix orientation. Life Sci 1995 56 1971-1982. 

Gatley SJ, Lan R, Volkow ND, Papas N, King P, Wong CT, Gilford AN, Pyatt B, Dewey SL, Makriyannis A. Imaging of the brain marijuana receptor—Development of a radioligand that binds to cannabinoid CB1 receptors in vivo. J Neurochem 1998 70 417 423. 

Howlett, AC, Mukhopadhyay S, Shim J-Y, Welsh WJ. Signal transduction of eicosanoid CB1 receptor ligands. Life Sci 1999 65 617-625. 

Sugiura T, Kotaka T, Nakane S, Miyashita T, Kondo S, Suhara Y, Takayama H, Waku K, Seki C, Baba N, Ishima Y. Evidence that the cannabinoid CB1 receptor is a 2-arachidonylglycerol receptor. J Biol Chem 1999 274 2794-2801. 

Varga KLK, Martin BR, Kunos G. Novel antagonist implicates the CB1 receptor in the hypotensive action of anandamide. Eur J Pharmacol 1995 278 279-283. 

The involvement of the cerebellum in the psychoactive effects of marijuana and in changes in rCMR is consistent with the view that THC interacts with the high concentration of CB1 receptors in this brain area. Decreases in the cerebellar rCMR in habitual marijuana users may reflect the effects of chronic exposure to the drug. Functions known to be associated with the cerebellum, such as motor coordination, proprioception, and learning, are adversely affected both during acute marijuana intoxication and in habitual users. 

The first attempt to develop a PET radioligand for imaging brain CB1 receptors involved modification of A8-THC by labeling with fluorine-18 in the hydrocarbon side chain [16,17], as shown in Figure 2. Unfortunately,... 

While we have not yet started human PET or SPECT studies, we have used AM281 to conduct fundamental studies of the CB1 receptor system in... 

A consequence of a very large receptor reserve for CB1 receptors would be that PET or SPECT could not be used to image the occupancy of the CB1 receptor by biologically significant doses of agonist drugs. This is... 

Figure 9 Graph of inhibition of acetylcholine release in superfused hippocampal slices versus CB1 receptor occupancy estimated from inhibition of [131I]AM281 binding.

Lan R, Gatley SJ, Makriyannis A. Preparation of iodine-123 labeled AM251, a potential SPECT radioligand for the brain cannabinoid CB1 receptor. J Labelled Comp Radiopharm 1996 38 875-881. 

Cosenza M, Gifford AN, Gatley SJ, Pyatt B, Liu Q, Makriyannis A, Volkow ND. Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281. Synapse 2000 38 477-482. 

Cohen, C., Perrault, G., Griebel, G., Soubrie, P. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology. 30 145, 2005. 

Le Foil, B., Goldberg, S.R. Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. J. Pharmacol. Exp. Ther. 312 875, 2005. 

Marijuana and hashish are derivatives of the cannabis sativa plant 919 Cannabinoid effects in the CNS are mediated by the CB1 receptor 919 Endocannabinoids are endogenous ligands for the CB1 receptor 919 Endocannabinoids serve as retrograde messengers 920 There are many similarities between endogenous opioid and cannabinoid systems 921... 

---