Cannabinoid receptor antagonist

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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 (CBR) and prevents their activation by endocannabinoids. They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development 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]

Contents

History

Cannabis plant Cannabis flowering.jpg
Cannabis plant

For centuries hashish and marijuana from the Indian hemp Cannabis sativa L. have been used for medicinal and recreational purposes. [4] [5] In 1840, Schlesinger S. was apparently the first investigator to obtain an active extract from the leaves and flowers of hemp. [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”. [7] [8] In 1964 the main active constituent of C. sativa L., Δ9-tetrahydrocannabinol (THC), was isolated and synthesized by Mechoulam's laboratory. [4] [9] Two types of cannabinoid receptors, CB1 and CB2, responsible for the effects of THC were discovered and cloned in the early 1990s. [1] [10] 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 (endocannabinoid), anandamide (arachidonoyl ethanolamide). Later on other endocannabinoids were found, for example 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: cannabinoid receptor 1 (CB1) and 2 (CB2). Both receptors are 7-transmembrane G-protein coupled receptors (GPCRs) which inhibit the accumulation of cyclic adenosine monophosphate within cells. [14] [15] CB1 receptors are present in highest concentration in the brain but can also be found in the periphery. CB2 receptors are mostly located in the immune and haematopoietic systems. [1] [14]

Endocannabinoids are eicosanoids acting as agonists for cannabinoid receptors, and they occur naturally in the body. [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. [13] There are two well-characterized endocannabinoids located in the brain and periphery. The first identified was anandamide (arachidonoyl ethanolamide), 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). [14]

Mechanism of action

Figure 1 Hypothetical model for the metabolic effects of CB1 receptor antagonists. (ECS=endocannabinoid system) Metabolic effects of CB1 antagonism.png
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 adenylyl cyclase and activate mitogen-activated protein (MAP) kinase. In addition, CB1 receptors inhibit presynaptic N- and P/Q-type calcium channels and activate inwardly rectifying 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 hypothalamic areas which are involved in central food intake control and feeding behavior. 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. [14] [16] Peripheral CB1 receptors are located in the gastrointestinal (GI) tract, liver and in adipose tissue. In the GI, CB1 receptors are located on nerve terminals in the intestines. Endocannabinoids act at the CB1 receptors to increase hunger and promote feeding and it is speculated that they decrease intestinal peristalsis and gastric emptying. Thus, antagonism at these receptors can inverse these effects. [14] Also, in peripheral tissues, antagonism of CB1 receptors increases insulin sensitivity and oxidation of 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 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. In 1994 the first selective cannabinoid antagonist, SR141716 (rimonabant), was introduced by Sanofi belonging to a family of 1,5-diarylpyrazoles. [10] [17]

Rimonabant

Figure 2 Chemical structure of rimonabant Rimonabant highlighted.svg
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) Two state model CB1 antagonists.png
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 Pharmacophore.png
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. [19] This can be explained by the two state-model of receptor activation in which receptors are in equilibrium between two states, active and inactive (R* and R). An agonist will stabilize the active state leading to activation, a 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. [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. This bond stabilizes the Lys192-Asp366 salt bridge of the intracellular end of 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 isosteres of rimonabant. [23] A general CB1 inverse agonist pharmacophore model can be extracted from the common features of these analogs, diarylpyrazoles (Figure 4). [20] 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. 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. [20] 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. [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 structure-activity relationship (SAR) within this chemical group. While most compounds described are less potent than SR141716, two of them are worth mentioning, SR147778 and 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.png AM251 CB1 antagonist.png
SR147778 AM251
NESS 0327.png O1248.png
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 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 (benzyloxy) and a polar (nitrile) functionality. Other six-membered ring analogs are for example pyrimidines and 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 sulfonyl group serves as a hydrogen bond acceptor. The 1,1-diaryl group is also present in derivatives such as the benzodioxoles and hydantoins. [2] [20]

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
Ibipinabant.svg Diarylimidazole derivative.png Diarylpyrrol carboxamide CB1 derivative.png
Type of
derivative		3,4-Diarylpyrazoline (Ibipinabant)4,5-Diarylimidazole1,5-Diarylpyrrole-3-carboxamides
Purine CB1 derivative.png Otenabant CP945598 CB1 antagonist.png 2 3 diarylpyridine CB1 derivative.png
Type of
derivative		 Purine (pyrimidine ring
fused to an imidazole ring)		Purine derivative (Otenabant)2,3-Diarylpyridine
Pyrimidine CB1 derivative.png Pyrazine CB1 derivative.png Azetidine CB1 derivative.png
Type of
derivative		 Pyrimidine Pyrazine Methylsulfonamide
azetidine
Benzodioxoles CB1 derivative.png Hydantoin CB1 derivative.png Taranabant MK0364 CB1 antagonist.png
Type of
derivative		 Benzodioxole Hydantoin Acyclic derivative
(Taranabant)

CB1 receptor antibodies

Antibodies against the CB1 receptor have been developed and introduced into clinical use in Russia. [31] They include brizantin (Russian:Бризантин®) and dietressa (Russian:Диетресса®). [31] Brizantin is indicated for the treatment of nicotine withdrawal and smoking cessation and dietressa is indicated for weight loss. [31] Dietressa is available over-the-counter in Russia. [31]

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. [32] On 5 November 2008 Sanofi-Aventis announced discontinuation of rimonabant clinical development program. [33]

Sanofi-Aventis has also discontinued development of surinabant (SR147778), a CB1 receptor antagonist for smoking cessation (31 October 2008). [34]

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. [35]

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. [36]

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. Among these initiatives 7TM Pharma has reported the development of TM38837.[ citation needed ] A review has now published on the approaches and compounds being pursued as peripherally restricted CB1 receptor blockers. [37]

See also

Related Research Articles

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.

<span class="mw-page-title-main">Cannabinoid receptor</span> Group of receptors to cannabinoid compounds

Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates– a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids; phytocannabinoids ; and synthetic cannabinoids. All endocannabinoids and phytocannabinoids are lipophilic.

<span class="mw-page-title-main">Rimonabant</span> Chemical compound

Rimonabant (also known as SR141716; trade names Acomplia, Zimulti) is an anorectic antiobesity drug approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in the United States. Rimonabant is an inverse agonist for the cannabinoid receptor CB1 and was first-in-class for clinical development.

<span class="mw-page-title-main">Cannabinol</span> Naturally-occurring cannabinoid

Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors. This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS).

<span class="mw-page-title-main">AM-251 (drug)</span> Chemical compound

AM-251 is an inverse agonist at the CB1 cannabinoid receptor. AM-251 is structurally very close to rimonabant; both are biarylpyrazole cannabinoid receptor antagonists. In AM-251, the p-chloro group attached to the phenyl substituent at C-5 of the pyrazole ring is replaced with a p-iodo group. The resulting compound exhibits slightly better binding affinity for the CB1 receptor (with a Ki value of 7.5 nM) than rimonabant, which has a Ki value of 11.5 nM, AM-251 is, however, about two-fold more selective for the CB1 receptor when compared to rimonabant. Like rimonabant, it is additionally a μ-opioid receptor antagonist that attenuates analgesic effects.

<span class="mw-page-title-main">Cannabinoid receptor 1</span> Mammalian protein found in Homo sapiens

Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene. The human CB1 receptor is expressed in the peripheral nervous system and central nervous system. It is activated by endocannabinoids, a group of retrograde neurotransmitters that include anandamide and 2-arachidonoylglycerol (2-AG); plant phytocannabinoids, such as docosatetraenoylethanolamide found in wild daga, the compound THC which is an active constituent of the psychoactive drug cannabis; and synthetic analogs of THC. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin (THCV).

<span class="mw-page-title-main">Cannabinoid receptor 2</span> Mammalian protein found in Homo sapiens

The cannabinoid receptor 2(CB2), is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. It is closely related to the cannabinoid receptor 1 (CB1), which is largely responsible for the efficacy of endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties of tetrahydrocannabinol (THC), the active agent in cannabis, and other phytocannabinoids. The principal endogenous ligand for the CB2 receptor is 2-Arachidonoylglycerol (2-AG).

<span class="mw-page-title-main">JWH-051</span> Chemical compound

JWH-051 is an analgesic drug which is a cannabinoid agonist. Its chemical structure is closely related to that of the potent cannabinoid agonist HU-210, with the only difference being the removal of the hydroxyl group at position 1 of the aromatic ring. It was discovered and named after John W. Huffman.

<span class="mw-page-title-main">NESS-0327</span> Chemical compound

NESS-0327 is a drug used in scientific research which acts as an extremely potent and selective antagonist of the cannabinoid receptor CB1. It is much more potent an antagonist, and more selective for the CB1 receptor over CB2, than the more commonly used ligand rimonabant, with a Ki at CB1 of 350fM (i.e. 0.00035nM) and a selectivity of over 60,000x for CB1 over CB2. Independently, two other groups have described only modest nanomolar CB1 affinity for this compound (125nM and 18.4nM). Also unlike rimonabant, NESS-0327 does not appear to act as an inverse agonist at higher doses, instead being a purely neutral antagonist which blocks the CB1 receptor but does not produce any physiological effect of its own.

<span class="mw-page-title-main">VCHSR</span> Chemical compound

VCHSR is a drug used in scientific research which acts as a selective antagonist of the cannabinoid receptor CB1. It is derived from the widely used CB1 antagonist rimonabant, and has similar potency and selectivity for the CB1 receptor, but has been modified to remove the hydrogen bonding capability in the C-3 substituent region, which removes the inverse agonist effect that rimonabant produces at high doses, so that VCHSR instead acts as a neutral antagonist, blocking the receptor but producing no physiological effect of its own.

<span class="mw-page-title-main">Ibipinabant</span> Chemical compound

Ibipinabant (SLV319, BMS-646,256) is a drug used in scientific research which acts as a potent and highly selective CB1 antagonist. It has potent anorectic effects in animals, and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists. SLV330, which is a structural analogue of Ibipinabant, was reported active in animal models related to the regulation of memory, cognition, as well as in addictive behavior. An atom-efficient synthesis of ibipinabant has been reported.

RVD-Hpα (pepcan-12) is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist. All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide. Recently it was shown that RVD-Hpα (also called Pepcan-12) is a potent negative allosteric modulator at CB1 receptors, together with other newly described N-terminally extended peptides (pepcans).

<span class="mw-page-title-main">AM-1221</span> Chemical compound

AM-1221 is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB2, with a Ki of 0.28 nM at CB2 and 52.3 nM at the CB1 receptor, giving it around 180 times selectivity for CB2. The 2-methyl and 6-nitro groups on the indole ring both tend to increase CB2 affinity while generally reducing affinity at CB1, explaining the high CB2 selectivity of AM-1221. However, despite this relatively high selectivity for CB2, its CB1 affinity is still too strong to make it useful as a truly selective CB2 agonist, so the related compound AM-1241 is generally preferred for research purposes.

<span class="mw-page-title-main">AM-630</span> Chemical compound

AM-630 (6-Iodopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2, with a Ki of 32.1 nM at CB2 and 165x selectivity over CB1, at which it acted as a weak partial agonist. It is used in the study of CB2 mediated responses and has been used to investigate the possible role of CB2 receptors in the brain. AM-630 is significant as one of the first indole derived cannabinoid ligands substituted on the 6-position of the indole ring, a position that has subsequently been found to be important in determining affinity and efficacy at both the CB1 and CB2 receptors, and has led to the development of many related derivatives.

<span class="mw-page-title-main">MN-25</span> Chemical compound

MN-25 (UR-12) is a drug invented by Bristol-Myers Squibb, that acts as a reasonably selective agonist of peripheral cannabinoid receptors. It has moderate affinity for CB2 receptors with a Ki of 11 nM, but 22x lower affinity for the psychoactive CB1 receptors with a Ki of 245 nM. The indole 2-methyl derivative has the ratio of affinities reversed however, with a Ki of 8 nM at CB1 and 29 nM at CB2, which contrasts with the usual trend of 2-methyl derivatives having increased selectivity for CB2 (cf. JWH-018 vs JWH-007, JWH-081 vs JWH-098).

<span class="mw-page-title-main">O-1269</span> Chemical compound

O-1269 is a drug that is a diarylpyrazole derivative, related to potent cannabinoid antagonist drugs such as rimonabant and surinabant. However O-1269 and several related drugs were unexpectedly found to act as full or partial agonists at the cannabinoid receptors rather than antagonists, and so produce the usual effects expected of cannabinoid agonists in animal tests, such as sedation and analgesic effects. The N-heptyl homolog O-1270 and the N-propyl homolog O-1399 also act as cannabinoid agonists with similar potency in vivo, despite weaker binding affinity at cannabinoid receptors compared to the pentyl homolog O-1269. Agonist-like and atypical cannabinoid activity has also been observed with a number of related compounds.

<span class="mw-page-title-main">AM-2389</span> Chemical compound

AM-2389 is a classical cannabinoid derivative which acts as a potent and reasonably selective agonist for the CB1 receptor, with a Ki of 0.16 nM, and 26x selectivity over the related CB2 receptor. It has high potency in animal tests of cannabinoid activity, and a medium duration of action. Replacing the 1',1'-dimethyl substitution of the dimethylheptyl side chain of classical cannabinoids with cyclopropyl or cyclopentyl results in higher potency than cyclobutyl, but only the cyclobutyl derivatives show selectivity for CB1 over CB2. High selectivity for CB1 over CB2 is difficult to achieve (cf. AM-906, AM-1235), as almost all commonly used CB1 agonists have similar or greater affinity for CB2 than CB1, and the only truly highly selective CB1 agonists known as of 2012 are eicosanoid derivatives such as O-1812.

<span class="mw-page-title-main">Drinabant</span> Chemical compound

Drinabant (INN; AVE-1625) is a drug that acts as a selective CB1 receptor antagonist, which was under investigation varyingly by Sanofi-Aventis as a treatment for obesity, schizophrenia, Alzheimer's disease, Parkinson's disease, and nicotine dependence. Though initially studied as a potential treatment for a variety of different medical conditions, Sanofi-Aventis eventually narrowed down the therapeutic indications of the compound to just appetite suppression. Drinabant reached phase IIb clinical trials for this purpose in the treatment of obesity but was shortly thereafter discontinued, likely due to the observation of severe psychiatric side effects including anxiety, depression, and thoughts of suicide in patients treated with the now-withdrawn rimonabant, another CB1 antagonist that was also under development by Sanofi-Aventis.

<span class="mw-page-title-main">JD5037</span> Chemical compound

JD5037 is an antiobesity drug candidate which acts as a peripherally-restricted cannabinoid inverse agonist at CB1 receptors. It is very selective for the CB1 subtype, with a Ki of 0.35nM, >700-fold higher affinity than it has for CB2 receptors.

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