Cannabinoid receptor antagonist
A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of
History
For centuries
Endocannabinoids and their signaling system
The
There are two main receptor types associated with the endocannabinoid signaling system:
Endocannabinoids are
Mechanism of action
CB1 receptors are coupled through Gi/o proteins and inhibit
CB1 receptors are highly expressed in
Drug design
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
Rimonabant
Rimonabant, also known by the systematic name [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride)], is a 1,5-diarylpyrazole CB1 receptor antagonist (Figure 2).[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. Rimonabant has shown clear clinical efficacy for the treatment of obesity.[18]
Binding
Binding of an agonist ligand to the CB1 receptor provokes a conformational change and leads to the active state of the receptor which is responsible for the signal transduction. However, there is an additional mechanism that can lead to the active state in the absence of ligand. As numerous other GPCRs, CB1 receptor displays a high level of constitutive activity and thus it can spontaneously adopt an active conformational state in the absence of agonist binding, keeping elevated basal levels of intracellular signaling.
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.
In the inactive state of CB1 rimonabant binds within the transmembrane-3-4-5-6 aromatic microdomain. The binding of rimonabant involves direct aromatic stacking interactions between its 2,4-dichlorophenyl ring and the Trp279/Phe200/Trp356 residues on the one side and the para-chlorophenyl ring and the Tyr275/Trp255/Phe278 residues on the other side. The lipophilic piperidinyl moiety fits nicely in a cavity formed by the amino acid residues Val196/Phe170/Leu387 and Met384 (Figure 4).[20][18][19][22]
Pharmacophore
Most CB1 antagonists reported so far are close analogs or
Structure-activity relationships
Optimal binding at the CB1 receptor requires a para-substituted phenyl ring at the pyrazole 5-position. The 5-substituent of the pyrazole is involved in receptor recognition and antagonism. The para-substituent of the phenyl ring could be chlorine, bromine or iodine, but it has been shown that an alkyl chain could also be tolerated.[20] Numbering of the central pyrazole ring is shown in Figure 2.
A 2,4-dichloro-substituted phenyl ring at the pyrazole 1-position is preferred for affinity as well as for the activity. It has been shown that additional
It is also favorable to have a ring substitution at the 3-carboxamide group, such as the 1-piperidinyl group in rimonabant.
Research has shown that the absence of the
Diarylpyrazole derivatives
SR141716 (rimonabant) analogs have recently been described by several groups, leading to a good understanding of the
SR147778 (surinabant), a second generation antagonist, has a longer duration of action than rimonabant and enhanced oral activity. 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. Another change is the replacement of the 5-phenyl chlorine substituent by bromine.[2][20][26]
The diarylpyrazole derivative, AM251, has been described where chlorine substituent has been replaced by iodine in the para position of the 5-phenyl ring. This derivative appeared to be more potent and selective than rimonabant.[11][18]
21 analogs possessing either an alkyl amide or an alkyl hydrazide of variant lengths in position 3 were synthesized. It was observed that affinity increases with increased carbon chain length up to five carbons. Also the amide analogs exhibited higher affinity than hydrazide analogs. However, none of these analogs possessed significantly greater affinity than rimonabant but nevertheless, they were slightly more selective than rimonabant for the CB1 receptor over the CB2 receptor.[18]
Several attempts have been made to increase the affinity of the diarylpyrazole derivatives by rigidifying the structure of rimonabant. In terms of the general pharmacophore model the units A, B and/or C are connected by additional bonds leading to rigid molecules. For example, the condensed polycyclic pyrazole NESS-0327 showed 5000 times more affinity for the CB1 receptor than rimonabant. However, this compound possesses a poor central bioavailability.[20][18]
Another compound, the indazole derivative O-1248, can be regarded as an analog of rimonabant wherein its 5-aryl group is fused to the pyrazole moiety. However, this structural modification resulted in a 67-fold decrease in CB1 receptor affinity.[20]
These diarylpyrazole derivatives of rimonabant are summarized in Table 1.
SR147778
|
AM251
|
NESS-0327 | O-1248 |
Other derivatives
Structurally different from the 1,5-diarylpyrazoles are the chemical series of the 3,4-diarylpyrazolines. 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.[2][20]
Another approach used to develop analogs of rimonabant was to replace central pyrazole ring by another
A large number of fused bicyclic derivatives of diaryl-pyrazole and imidazoles have been reported. An example of these is a purine derivative where a pyrimidine ring is fused to an imidazole ring.[2] Otenabant (CP-945,598) is an example of a fused bicyclic derivative developed by Pfizer.[27]
Several research groups have studied six-membered ring pyrazole
In addition to the five and six-membered ring analogs there are other cyclic derivatives such as the azetidines. One example is the methylsulfonamide azetidine derivative which has a 1,1-diaryl group that mimics the 1,5-diaryl moiety of the diarylpyrazoles. The
Acyclic analogs have also been reported. These analogs contain a 1,2-diaryl motif which corresponds to the 1,5-diaryl substituents of rimonabant.[2] An example of an acyclic analog is taranabant (MK-0364) developed by Merck.[27]
Determination of crystal structures of CB1 and CB2 receptors facilitated the design of structurally different CBR antagonists.[28][29][30]
Representatives of these analogs are summarized in Table 2.
Type of derivative |
3,4-Diarylpyrazoline (Ibipinabant) | 4,5-Diarylimidazole | 1,5-Diarylpyrrole-3-carboxamides |
Type of derivative |
Purine (pyrimidine ring fused to an imidazole ring) |
Purine derivative (Otenabant) | 2,3-Diarylpyridine |
Type of derivative |
Pyrimidine | Pyrazine | Methylsulfonamide azetidine |
Type of derivative |
Benzodioxole
|
Hydantoin | Acyclic derivative (Taranabant) |
CB1 receptor antibodies
Current status
Rimonabant (Acomplia) has been approved in the European Union (EU) since June 2006 for the treatment of obesity. 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.[33] On 5 November 2008 Sanofi-Aventis announced discontinuation of rimonabant clinical development program.[34]
Sanofi-Aventis has also discontinued development of surinabant (SR147778), a CB1 receptor antagonist for smoking cessation (31 October 2008).[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. Data from Phase III clinical trial showed that greater efficacy and more adverse effects were associated with the higher doses of taranabant and it was determined that the overall profile of taranabant does not support further development for obesity.[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. According to Pfizer their decision was based on changing regulatory perspectives on the risk/benefit profile of the CB1 class and likely new regulatory requirements for approval.[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
See also
References
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