Cannabinoid receptor antagonist
Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain.
The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists.
THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.
[3] For centuries hashish and marijuana from the Indian hemp Cannabis sativa L. have been used for medicinal and recreational purposes.
[6] A few years later, in 1848, Decourtive E. described the preparation of an ethanol extract that on evaporation of the solvent gave a dark resin, which he named "cannabin".
This fact led to the logical extension that blocking of the cannabinoid receptors might be useful in decreasing appetite and food intake.
[9] Cannabinoid receptor-related processes are, for example, involved in cognition; memory; anxiety; control of appetite; emesis; motor behavior; sensory, autonomic, neuroendocrine, and immune responses; and inflammatory effects.
[4][16] CB1 receptors are highly expressed in hypothalamic areas which are involved in central food intake control and feeding behavior.
Endocannabinoids act at the CB1 receptors to increase hunger and promote feeding and it is speculated that they decrease intestinal peristalsis and gastric emptying.
[14] Also, in peripheral tissues, antagonism of CB1 receptors increases insulin sensitivity and oxidation of fatty acids in muscles and the liver.
The first approach to develop cannabinoid antagonists in the late 1980s was to modify the structure of THC, but the results were disappointing.
In the early 1990s new family of cannabinoid agonists was discovered from the NSAID (non-steroidal anti-inflammatory) drug pravadoline which led to the discovery of aminoalkyl indole antagonists with some but limited success.
As the search based on the structure of agonists was disappointing it was no surprise that the first potent and selective cannabinoid antagonist belonged to an entirely new chemical family.
[17] Rimonabant is not only a potent and highly selective ligand of the CB1 receptor, but it is also orally active and antagonizes most of the effects of cannabinoid agonists, such as THC, both in vitro and in vivo.
[19] Rimonabant has been reported in many cases to behave as an inverse agonist rather than as a neutral antagonist and it is likely that it binds preferentially to the inactive state of the CB1, thereby decreasing the activation of the signaling pathway.
[20][21] The key binding interaction is a hydrogen bond formed between the carbonyl group of rimonabant and the Lys192 residue of the CB1 receptor.
The lipophilic piperidinyl moiety fits nicely in a cavity formed by the amino acid residues Val196/Phe170/Leu387 and Met384 (Figure 4).
[23] A general CB1 inverse agonist pharmacophore model can be extracted from the common features of these analogs, diarylpyrazoles (Figure 4).
[20] Replacement of the amino piperidinyl substituent by alkyl amides, ethers, ketones, alcohols or alkanes resulted mostly in decreased affinity.
This enhanced duration of action is probably due to the presence of the more metabolically stable ethyl group at the 4-position of its pyrazole ring.
In terms of the general pharmacophore model the units A, B and/or C are connected by additional bonds leading to rigid molecules.
Within this series is SLV-319 (ibipinabant), a potent CB1 antagonist which is about 1000-fold more selective for CB1 compared with CB2 and displays in vivo activity similar to rimonabant.
The structure of this compound demonstrates the possibility that the amide moiety of rimonabant could be split into a lipophilic (benzyloxy) and a polar (nitrile) functionality.
On 23 October 2008 the European Medicines Agency (EMEA) has recommended the suspension of the marketing authorization across the EU for Acomplia from Sanofi-Aventis based on the risk of serious psychiatric disorders.
[35] Merck has stated in its press release on 2 October 2008 that they will not seek regulatory approval for taranabant (MK-0364) to treat obesity and will discontinue its Phase III clinical development program.
[36] Another pharmaceutical company, Pfizer, terminated the Phase III development program for its obesity compound otenabant (CP-945,598), a selective antagonist of the CB1 receptor.
[37] A number of initiatives have been published to develop CB1 antagonists that target only peripheral CB1 receptors by restricting their ability to cross the blood brain barrier.
[citation needed] A review has now published on the approaches and compounds being pursued as peripherally restricted CB1 receptor blockers.
