A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of
cannabinoid
Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
ergic
drug
A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
that binds to
cannabinoid receptor
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 cann ...
s (CBR) and prevents their activation by
endocannabinoid
Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
s. They include
antagonist
An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.[inverse agonist
In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
A neutral antagonist has no activity in the absence of an agonist or inverse agon ...](_b ...<br></span></div>s, <div class=)
s, and
antibodies
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
of CBRs. The discovery of the
endocannabinoid system
The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the central nervous system ( ...
led to the development of
CB1 receptor antagonists. The first CBR inverse agonist,
rimonabant
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known as SR141716; trade names Acomplia, Zimulti) is an anorectic antiobesity drug approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in the United State ...
, was described in 1994. Rimonabant blocks the CB
1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of
obesity
Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
worldwide is increasing dramatically and has a great impact on
public health
Public health is "the science and art of preventing disease, prolonging life and promoting health through the organized efforts and informed choices of society, organizations, public and private, communities and individuals". Analyzing the de ...
. 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
Cannabidiol (CBD) is a phytocannabinoid, one of 113 identified cannabinoids in ''Cannabis'', along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. Medically, it is an anticonvulsant used to treat multiple f ...
(CBD), a naturally occurring cannabinoid and a non-competitive CB
1/CB
2 receptor antagonist, as well as
Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of
THC via direct blockade of cannabinoid CB
1 receptors, thus behaving like first-generation CB
1 receptor inverse agonists, such as
rimonabant
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 State ...
. CBD is a very low-affinity CB
1 ligand, that can nevertheless affect CB
1 receptor activity ''in vivo'' in an indirect manner, while THCV is a high-affinity CB
1 receptor ligand and potent antagonist ''in vitro'' and yet only occasionally produces effects ''in vivo'' resulting from CB
1 receptor antagonism. THCV has also high affinity for CB
2 receptors and signals as a
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...
, differing from both CBD and rimonabant.
History
For centuries
hashish
Hashish (; ), usually abbreviated as hash, is a Compression (physics), compressed form of resin (trichomes) derived from the cannabis flowers. European Monitoring Centre for Drugs and Drug Addiction, Lisbon, As a Psychoactive drug, psychoactive ...
and
marijuana
Cannabis (), commonly known as marijuana (), weed, pot, and ganja, List of slang names for cannabis, among other names, is a non-chemically uniform psychoactive drug from the ''Cannabis'' plant. Native to Central or South Asia, cannabis has ...
from the Indian hemp ''
Cannabis sativa
''Cannabis sativa'' is an annual Herbaceous plant, herbaceous flowering plant. The species was first classified by Carl Linnaeus in 1753. The specific epithet ''Sativum, sativa'' means 'cultivated'. Indigenous to East Asia, Eastern Asia, the pla ...
'' L. have been used for medicinal and recreational purposes.
In 1840, Schlesinger S. was apparently the first investigator to obtain an active extract from the leaves and flowers of hemp. 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". In 1964 the main active constituent of ''C. sativa'' L., Δ
9-tetrahydrocannabinol (
THC), was isolated and synthesized by
Mechoulam's laboratory.
Two types of
cannabinoid receptors, CB
1 and CB
2, 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
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...
occur naturally in the body. This search led to the discovery of the first endogenous cannabinoid (endocannabinoid),
anandamide
Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...
(arachidonoyl ethanolamide). 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. 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.
It was then discovered that the blockage of the CB
1 receptor represented a new pharmacological target. The first specific CB
1 receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...
/
inverse agonist
In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
A neutral antagonist has no activity in the absence of an agonist or inverse agon ...
was
rimonabant
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 State ...
, discovered in 1994.
Endocannabinoids and their signaling system
The
endogenous cannabinoid system includes cannabinoid receptors, their endogenous ligands (endocannabinoids) and enzymes for their synthesis and degradation.
There are two main receptor types associated with the endocannabinoid signaling system:
cannabinoid receptor 1
Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the ''CNR1'' gene. And discovered, by determination and characterization in 1988, and cloned in 1990 for the first time. The human CB1 recep ...
(CB
1) and 2 (
CB2). Both receptors are 7-transmembrane G-protein coupled receptors (
GPCRs) which inhibit the accumulation of
cyclic adenosine monophosphate
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine tri ...
within cells.
CB
1 receptors are present in highest concentration in the brain but can also be found in the periphery. CB
2 receptors are mostly located in the immune and
haematopoietic systems.
Endocannabinoids are
eicosanoids
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub ...
acting as agonists for cannabinoid receptors, and they occur naturally in the body.
Cannabinoid receptor-related processes are, for example, involved in cognition; memory; anxiety; control of appetite;
emesis
Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteritis, pregna ...
; motor behavior;
sensory,
autonomic,
neuroendocrine
Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules ( hormones) into the blood. In this way they b ...
, and immune responses; and inflammatory effects.
There are two well-characterized endocannabinoids located in the brain and
periphery. The first identified was
anandamide
Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...
(arachidonoyl ethanolamide), and the second was 2-AG (
2-arachidonoyl glycerol
2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is presen ...
). Additional endocannabinoids include
virodhamine
Virodhamine (''O''-arachidonoyl ethanolamine; O-AEA) is an endocannabinoid and a nonclassic eicosanoid, derived from arachidonic acid. ''O''-Arachidonoyl ethanolamine is arachidonic acid and ethanolamine joined by an ester linkage, the opposit ...
(O-arachidonoyl ethanolamine),
noladin ether (2-arachidonoyl glyceryl ether) and NADA (
N-arachidonoyl dopamine).
Mechanism of action
CB
1 receptors are coupled through G
i/o proteins and inhibit
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
and activate
mitogen-activated protein
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammato ...
(MAP) kinase. In addition, CB
1 receptors inhibit presynaptic N- and P/Q-type calcium channels and activate inwardly rectifying
potassium channels
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of ...
.
CB
1 antagonists produce inverse cannabimimetic effects that are opposite in direction from those produced by agonists for these receptors.
CB
1 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, CB
1 antagonists might indirectly inhibit the dopamine-mediated rewarding properties of food.
Peripheral CB
1 receptors are located in the gastrointestinal (GI) tract, liver and in adipose tissue. In the GI, CB
1 receptors are located on nerve terminals in the intestines. Endocannabinoids act at the CB
1 receptors to increase hunger and promote feeding and it is speculated that they decrease intestinal
peristalsis
Peristalsis ( , ) is a type of intestinal motility, characterized by symmetry in biology#Radial symmetry, radially symmetrical contraction and relaxation of muscles that propagate in a wave down a tube, in an wikt:anterograde, anterograde dir ...
and gastric emptying. Thus, antagonism at these receptors can inverse these effects.
Also, in peripheral tissues, antagonism of CB
1 receptors increases
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
sensitivity and oxidation of
fatty acids
In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
in muscles and the liver.
A hypothetical scheme for the metabolic effects of CB
1 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 drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
(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
Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
belonging to a family of 1,5-diarylpyrazoles.
Rimonabant
Rimonabant, also known by the systematic name
'N''-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1''H''-pyrazole-3-carboxamidehydrochloride) is a 1,5-diarylpyrazole CB
1 receptor antagonist (Figure 2).
Rimonabant is not only a potent and highly selective ligand of the CB
1 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.
Binding
Binding of an agonist ligand to the CB
1 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, CB
1 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.
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
A receptor antagonist is a type of Receptor (biochemistry), receptor ligand (biochemistry), ligand or drug that blocks or dampens a biological response by binding to and blocking a Receptor (biochemistry), receptor rather than activating it like ...
binds equally to active and inactive states, whereas an
inverse agonist
In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
A neutral antagonist has no activity in the absence of an agonist or inverse agon ...
will preferentially stabilize the inactive state (Figure 3).
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 CB
1, thereby decreasing the activation of the signaling pathway.
The key binding interaction is a
hydrogen bond
In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...
formed between the
carbonyl
In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...
group of rimonabant and the Lys192 residue of the CB
1 receptor. This bond stabilizes the Lys192-Asp366
salt bridge
In electrochemistry, a salt bridge or ion bridge is an essential laboratory device discovered over 100 years ago. It contains an electrolyte solution, typically an inert solution, used to connect the Redox, oxidation and reduction Half cell, ...
of the intracellular end of
transmembrane
A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
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.
In the inactive state of CB
1 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).
Pharmacophore
Most CB
1 antagonists reported so far are close analogs or
isosteres of rimonabant.
A general CB
1 inverse agonist
pharmacophore model can be extracted from the common features of these analogs, diarylpyrazoles (Figure 4).
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.
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
Pyrazole is an organic compound with the chemical formula, formula . It is a heterocycle characterized as an azole with a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in Arene substitution pattern, ortho-substi ...
ring and unit D represents the carbonyl group which serves as the hydrogen bond acceptor. Unit E represents a lipophilic aminopiperidinyl moiety.
Structure-activity relationships
Optimal binding at the CB
1 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.
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
The halogens () are a group (periodic table), group in the periodic table consisting of six chemically related chemical element, elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the radioactive elements astatine (At) and ten ...
on this phenyl ring decrease affinity.
It is also favorable to have a ring substitution at the 3-carboxamide group, such as the 1-piperidinyl group in rimonabant.
Replacement of the amino piperidinyl substituent by
alkyl
In organic chemistry, an alkyl group is an alkane missing one hydrogen.
The term ''alkyl'' is intentionally unspecific to include many possible substitutions.
An acyclic alkyl has the general formula of . A cycloalkyl group is derived from a cy ...
amides,
ethers,
ketones
In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
,
alcohols
In chemistry, an alcohol (), is a type of organic compound that carries at least one hydroxyl () functional group bound to a Saturated and unsaturated compounds, saturated carbon atom. Alcohols range from the simple, like methanol and ethanol ...
or
alkanes
In organic chemistry, an alkane, or paraffin (a historical trivial name that also has other meanings), is an acyclic saturated hydrocarbon. In other words, an alkane consists of hydrogen and carbon atoms arranged in a tree structure in whi ...
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.
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 CB
1 receptor.
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.
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.
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.
21 analogs possessing either an alkyl amide or an alkyl
hydrazide
Hydrazides in organic chemistry are a class of organic compounds with the formula where R is acyl (), sulfonyl (), phosphoryl (), phosphonyl () and similar groups (chalcogen analogs are included, for example sulfur analogs called thiohydrazide ...
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 CB
1 receptor over the CB
2 receptor.
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 CB
1 receptor than rimonabant. However, this compound possesses a poor central
bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
.
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 CB
1 receptor affinity.
These diarylpyrazole derivatives of rimonabant are summarized in Table 1.
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 CB
1 antagonist which is about 1000-fold more selective for CB
1 compared with CB
2 and displays ''in vivo'' activity similar to rimonabant.
Another approach used to develop analogs of rimonabant was to replace central pyrazole ring by another
heterocycle
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...
. An example of this approach are 4,5-diarylimidazoles and 1,5-diarylpyrrole-3-carboxamides.
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
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The oth ...
ring is fused to an
imidazole
Imidazole (ImH) is an organic compound with the formula . It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. It can be classified as a heterocycle, specifically as a diazole.
Many natural products, ...
ring.
Otenabant (CP-945,598) is an example of a fused bicyclic derivative developed by
Pfizer
Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...
.
Several research groups have studied six-membered ring pyrazole
bioisostere
In medicinal chemistry, bioisosteres are chemical substituents or groups with similar physical or chemical properties which produce broadly similar biological properties in the same chemical compound. In drug design, the purpose of exchanging one b ...
s. For example, one 2,3-diarylpyridine derivative was shown to be potent and selective CB
1 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.
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.
Acyclic analogs have also been reported. 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.
Determination of crystal structures of CB
1 and CB
2 receptors facilitated the design of structurally different CBR antagonists.
Representatives of these analogs are summarized in Table 2.
CB1 receptor antibodies
Antibodies
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
against the CB
1 receptor have been developed and introduced into clinical use in
Russia
Russia, or the Russian Federation, is a country spanning Eastern Europe and North Asia. It is the list of countries and dependencies by area, largest country in the world, and extends across Time in Russia, eleven time zones, sharing Borders ...
.
They include
brizantin () and
dietressa ().
Brizantin is indicated for the treatment of
nicotine withdrawal and
smoking cessation
Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is Addiction, addictive and can cause Substance dependence, dependence. As a resu ...
and dietressa is indicated for
weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...
.
Dietressa is available
over-the-counter
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid pres ...
in Russia.
Current status
Rimonabant (Acomplia) has been approved in the
European Union
The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are Geography of the European Union, located primarily in Europe. The u ...
(EU) since June 2006 for the treatment of obesity. On 23 October 2008 the
European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
(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. On 5 November 2008 Sanofi-Aventis announced discontinuation of rimonabant clinical development program.
Sanofi-Aventis has also discontinued development of surinabant (SR147778), a CB
1 receptor antagonist for smoking cessation (31 October 2008).
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.
Another pharmaceutical company, Pfizer, terminated the Phase III development program for its obesity compound otenabant (CP-945,598), a selective antagonist of the CB
1 receptor. According to Pfizer their decision was based on changing regulatory perspectives on the risk/benefit profile of the CB
1 class and likely new regulatory requirements for approval.
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.
A review has now published on the approaches and compounds being pursued as peripherally restricted CB
1 receptor blockers.
See also
*
Endocannabinoid enhancer
*
Endocannabinoid reuptake inhibitor
References
{{DEFAULTSORT:Cannabinoid Receptor Antagonist
Hallucinogen antidotes