Cannabinoid receptor antagonist

Source: Wikipedia, the free encyclopedia.

A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of

CB1 receptor antagonists. The first CBR inverse agonist, rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists.[1][2] Cannabidiol (CBD), a naturally occurring cannabinoid and a non-competitive CB1/CB2 receptor antagonist, as well as Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB1 ligand, that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.[3]

History

Cannabis plant

For centuries

2-AG (2-arachidonoyl glycerol).[4] These findings raised further questions about the pharmacological and physiological role of the cannabinoid system. This revived the research on cannabinoid receptor antagonists which were expected to help answer these questions.[10] The use of the cannabinoid agonist, THC, in its many preparations to enhance appetite is a well known fact. This fact led to the logical extension that blocking of the cannabinoid receptors might be useful in decreasing appetite and food intake.[11] It was then discovered that the blockage of the CB1 receptor represented a new pharmacological target. The first specific CB1 receptor antagonist / inverse agonist was rimonabant, discovered in 1994.[10][11][12]

Endocannabinoids and their signaling system

The

endogenous cannabinoid system includes cannabinoid receptors, their endogenous ligands (endocannabinoids) and enzymes for their synthesis and degradation.[13]

There are two main receptor types associated with the endocannabinoid signaling system:

Endocannabinoids are

neuroendocrine, and immune responses; and inflammatory effects.[13]
There are two well-characterized endocannabinoids located in the brain and

Mechanism of action

Figure 1 Hypothetical model for the metabolic effects of CB1 receptor antagonists. (ECS=endocannabinoid system)

CB1 receptors are coupled through Gi/o proteins and inhibit

potassium channels.[4][11] CB1 antagonists produce inverse cannabimimetic effects that are opposite in direction from those produced by agonists for these receptors.[4][16]

CB1 receptors are highly expressed in

fatty acids in muscles and the liver.[1]
A hypothetical scheme for the metabolic effects of CB1 receptor antagonists is shown in Figure 1.

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

SR141716 (rimonabant), was introduced by Sanofi belonging to a family of 1,5-diarylpyrazoles.[10][17]

Rimonabant

Figure 2 Chemical structure of rimonabant
Figure 3 Schematic representation of the two state-model of CB1 receptor activation, in which receptors are in equilibrium between two states, active and inactive (R* and R)
Figure 4 A general CB1 receptor inverse agonist pharmacophore model. Putative CB1 receptor amino acid side chain residues in receptor-ligand interaction are shown. Rimonabant is taken as a representative example below. The applied colors indicate the mutual properties with the general CB1 pharmacophore

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.

neutral antagonist binds equally to active and inactive states, whereas an inverse agonist will preferentially stabilize the inactive state (Figure 3).[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.

transmembrane helices 3 and 6 (Figure 4). This specific salt bridge is present in the inactive state of the receptor but absent in the active state.[20][21]

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

hydrogen bond acceptor unit, D, connects C with a cyclic lipophilic part, E. In some cases unit E directly connects to C.[20][23] In Figure 4 rimonabant is used as an example. Unit A represents a 4-chlorophenyl group and unit B a 2,4-dichlorophenyl ring. Unit C is the central pyrazole ring and unit D represents the carbonyl group which serves as the hydrogen bond acceptor. Unit E represents a lipophilic aminopiperidinyl moiety.[20]

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

halogens on this phenyl ring decrease affinity.[20]

It is also favorable to have a ring substitution at the 3-carboxamide group, such as the 1-piperidinyl group in rimonabant.

pentyl or a heptyl chain gave the compounds agonistic properties. Based on these results it was concluded that the pyrazole 3-position seems to be involved in agonism, while the 1-,4-,5-positions appear to be involved in antagonism.[18]

Research has shown that the absence of the

carboxamide oxygen results in decreased affinity. Furthermore, the presence of carboxamide oxygen contributes in conferring the inverse agonist properties, whereas analogs lacking this oxygen are found to be neutral antagonists. These results support the hypothesis that the carboxamide oxygen forms a hydrogen bond with Lys192 residue at the CB1 receptor.[24]

Diarylpyrazole derivatives

SR141716 (rimonabant) analogs have recently been described by several groups, leading to a good understanding of the

AM251, although both may have action at mu opioid receptors as well.[25][2]

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.

Table 1 Diarylpyrazole derivatives of rimonabant
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

heterocycle. An example of this approach are 4,5-diarylimidazoles and 1,5-diarylpyrrole-3-carboxamides.[2]

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

pyrazines.[2]

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.

Table 2 Representatives of non-diarylpyrazole derivatives
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

over-the-counter in Russia.[31][32]

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

] A review has now published on the approaches and compounds being pursued as peripherally restricted CB1 receptor blockers.[38]

See also

References

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