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. Rimonabant has been approved in the European Union since June 2006 for the treatment of obesity. On 23 October 2008 the European Medicines Agency has recommended the suspension of the marketing authorization across the EU for Acomplia from Sanofi-Aventis based on the risk of serious psychiatric disorders.
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. Sanofi-Aventis has also discontinued development of surinabant , a CB1 receptor antagonist for smoking cessation . These analogs contain a 1,2-diaryl motif which corresponds to the 1,5-diaryl substituents of rimonabant. An example of an acyclic analog is taranabant (MK-0364) developed by Merck.
This pharmacophore contains a cyclic core, C, (e.g. pyrazole in rimonabant) substituted by two aromatic moieties, A and B. A hydrogen bond acceptor unit, D, connects C with a cyclic lipophilic part, E. Unit A represents a 4-chlorophenyl group and unit B a 2,4-dichlorophenyl ring.
Replacement of the amino piperidinyl substituent by alkyl amides, ethers, ketones, alcohols or alkanes resulted mostly in decreased affinity. Replacement of the piperidinyl by 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. Endocannabinoids are eicosanoids acting as agonists for cannabinoid receptors, and they occur naturally in the body.
The key binding interaction is a hydrogen bond formed between the carbonyl group of rimonabant and the Lys192 residue of the CB1 receptor. This bond stabilizes the Lys192-Asp366 salt bridge of the intracellular end of transmembrane helices 3 and 6 . This specific salt bridge is present in the inactive state of the receptor but absent in the active state. The diarylpyrazole derivative, AM251, has been described where chlorine substituent has been replaced by iodine in the para position of the 5-phenyl ring. It is also favorable to have a ring substitution at the 3-carboxamide group, such as the 1-piperidinyl group in rimonabant.
Several research groups have studied six-membered ring pyrazole bioisosteres. For example, one 2,3-diarylpyridine derivative was shown to be potent and selective CB1 inverse agonist. The structure of this compound demonstrates the possibility that the amide moiety of rimonabant could be split into a lipophilic and a polar functionality.
It was observed that affinity increases with increased carbon chain length up to five carbons. 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. Optimal binding at the CB1 receptor requires a para-substituted phenyl ring at the pyrazole 5-position.
The 1,1-diaryl group is also present in derivatives such as the benzodioxoles and hydantoins. Structurally different from the 1,5-diarylpyrazoles are the chemical series of the 3,4-diarylpyrazolines. Within this series is SLV-319 , a potent CB1 antagonist which is about 1000-fold more selective for CB1 compared with CB2 and displays in vivo activity similar to rimonabant. SR , a second generation antagonist, has a longer duration of action than rimonabant and enhanced oral activity.
The first identified was anandamide , and the second was 2-AG (2-arachidonoyl glycerol). Additional endocannabinoids include virodhamine (O-arachidonoyl ethanolamine), noladin ether (2-arachidonoyl glyceryl ether) and NADA (N-arachidonoyl dopamine). 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.
Sativa L., Δ9-tetrahydrocannabinol , was isolated and synthesized by Mechoulam’s laboratory. Two types of cannabinoid receptors, CB1 and CB2, responsible for the effects of THC were discovered and cloned in the early 1990s. Once cannabinoid receptors had been discovered, it became important to establish whether their agonists occur naturally in the body. This search led to the discovery of the first endogenous cannabinoid , anandamide . Later on other endocannabinoids were found, for example 2-AG (2-arachidonoyl glycerol). These findings raised further questions about the pharmacological and physiological role of the cannabinoid system.
Unit C is the central pyrazole ring and unit D represents the carbonyl group which serves as the hydrogen bond acceptor. 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 Delta 8 Cartridges 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. In 1994 the first selective cannabinoid antagonist, SR , was introduced by Sanofi belonging to a family of 1,5-diarylpyrazoles.
This revived the research on cannabinoid receptor antagonists which were expected to help answer these questions. 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.
CB1 antagonists produce inverse cannabimimetic effects that are opposite in direction from those produced by agonists for these receptors. 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.
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. 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 . 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. CB1 receptors are highly expressed in hypothalamic areas which are involved in central food intake control and feeding behavior.
On July 12, 2016 the New York City Emergency Medical Services responded to a “mass casualty event” in Brooklyn, New York, where 33 people ranging in age from 25 to 59 years old were adversely affected by the drug. Screening for the more usual drugs of abuse was negative in all 8 patients. AMB-FUBINACA itself was found in a sample from the product smoked by another patient. The metabolite was identified after 10 days and the AMB-FUBINACA was only confirmed 17 days after the incident.
This strongly indicates that the cannabinoid system is directly involved in feeding regulation. These regions are also interconnected with the mesolimbic dopamine pathway, the so-called “reward” system. Therefore, CB1 antagonists might indirectly inhibit the dopamine-mediated rewarding properties of food. Peripheral CB1 receptors are located in the gastrointestinal tract, liver and in adipose tissue. Endocannabinoids act at the CB1 receptors to increase hunger and promote feeding and it is speculated that they decrease intestinal peristalsis and gastric emptying.
The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists. Cannabidiol , a naturally occurring cannabinoid, is a non-competitive CB1/CB2 receptor antagonist. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant. For centuries hashish and marijuana from the Indian hemp Cannabis sativa L. Was apparently the first investigator to obtain an active extract from the leaves and flowers of hemp. Described the preparation of an ethanol extract that on evaporation of the solvent gave a dark resin, which he named “cannabin”.
Also, in peripheral tissues, antagonism of CB1 receptors increases insulin sensitivity and oxidation of fatty acids in muscles and the liver. A hypothetical scheme for the metabolic effects of CB1 receptor antagonists is shown in Figure 1. 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.
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. Most CB1 What is a delta 8 gummy? antagonists reported so far are close analogs or isosteres of rimonabant. A general CB1 inverse agonist pharmacophore model can be extracted from the common features of these analogs, diarylpyrazoles .
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. Otenabant (CP-945,598) is an example of a fused bicyclic derivative developed What is a delta 8 gummy? by Pfizer. CB1 receptors are coupled through Gi/o proteins and inhibit adenylyl cyclase and activate mitogen-activated protein kinase. In addition, CB1 receptors inhibit presynaptic N- and P/Q-type calcium channels and activate inwardly rectifying potassium channels.
A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors and prevents their activation by endocannabinoids. The discovery of the endocannabinoid system led to the development of CB1 receptor antagonists. 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.