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Cannabinoid receptor modulator

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Cannabinoid receptor modulators are a series of either natural or synthetic chemical ligands that can specifically bind to cannabinoid receptors (belonging to G protein-coupled receptor), mainly including the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2), to either induce the conformational change of the receptor (by allosteric modulator), to regulate the intracellular signal transduction of the receptor (upregulation by agonist, downregulation by inverse agonist), or to exert an occupational effect on the receptor without affecting the intrinsic activity (by antagonist)[1][2]. These binding actions on the cannabinoid receptor can subsequently alternate our physiological functions in order to achieve multiple therapeutic purposes, including but not limited to chronic pain, chemotherapy-induced nausea and vomiting, substance abuse, and diabetes[3]. The subtypes of cannabinoid receptors are discovered around 1980 to 1990[4], which was also the starting period for its modulator development[3]. Besides, relevant legislations in several countries such as the US[5], the UK[6] and Mainland China[7] have kept developing and updating with the contemporary clinical studies.

Pharmacology

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Cannabinoid receptors

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(Main Article: Cannabinoid receptor)

Figure 1: Structural comparison between CB1 and CB2[1]

Cannabinoid receptors are discovered to have two major subtypes[1][2] — cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), which are categorised as the G protein-coupled receptor consisting of seven transmembrane protein domains. After activation by its ligand binding, the 𝛼 subunit of G protein (Gi/o) is dissociated to exert an inhibition on adenylyl cyclase to prevent the cAMP production from ATP that promotes the phosphorylation of targeted proteins by activating PKA. In contrast, its remaining 𝛽𝛾 subunit complex initiates the Akt/PKB signalling pathway, further triggering the MAPK/ERK pathway[1][8].

Figure 2: Overview of the signalling pathway comparison between CB1 and CB2[1]
Figure 3[9]: Overview of pharmacological actions by ligands/modulators on common receptors: A binds on active site (B) of the enzyme (E) to exert agonistic or antagonistic effect (4). C is an allosteric modulator binding on the other site (D) to either: cause conformational change to B (1), regulate signal transduction from A (2), or exert an pharmacological effect to the enzyme (3). Receptor response is then conveyed to subsequent pathway (F).

Categories of CB modulators

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Both CB1 and CB2 can experience agonism, antagonism, or allosteric modification when relevant ligands/modulators bind to them causing different degrees of receptor activity alternation[10][11].

Agonists can increase receptor activity by activating the receptor[12]. Partial agonists have a similar action as agonists, but their maximum effect (or efficacy) does not achieve 100% activity of the receptor even with their full occupation on the receptors[12]. Inverse agonists bind to the receptor but exert an opposite pharmacological effect of the agonist to the receptor[13]. Antagonists do not activate receptors and usually exhibit an occupational effect on them without changing their intrinsic activity[13]. Allosteric modulators, possessing the ability of positive or negative allosteric modification, bind to a site of the receptors apart from the active site to induce their conformational changes that can either regulate the ligand affinity or the intracellular signal transduction[11][14].    

Figure 4: Overview of receptor activity affected by (from top to bottom) full agonist, partial agonist, neutral antagonist and inverse agonist.[11]

List of some CB modulators

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Agonist[15][16][17]

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Non-selective agonist: WIN 55,212-2

Non-selective full agonists: CP-55940,  2-Arachidonoylglycerol (2-AG)

CB2-targeted: fenofibrate

Partial agonist[15]

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Non-selective: Anandamide (AEA), Δ9-tetrahydrocannabinol (THC)[15], Cannabidiol (CBD)

CB1-targeted: CB2-targeted:  

Inverse agonist[13]

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CB1-targeted:
  • Taranabant
  • Rimonabant
  • Ibipinabant
  • AM251
 CB2-targeted:  

CB1-targeted neutral antagonist:

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Allosteric modulator[19]

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Positive allosteric modulation (PAM)

CB1-targeted[10]: CB2-targeted:  
  • IQM311
  • CB2R PAM (C2)

Negative allosteric modulation (NAM)

CB1-targeted[20][21]:

Pharmacokinetics[3]

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Absorption

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In general, the oral absorption of cannabinoid receptor modulators is relatively low due to their high susceptibility to first-pass effect in the liver. Users tend to take these modulators via inhalational or transdermal route to receive a quicker onset of action.

Distribution

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Because of the high lipophilic nature, the majority of the modulators can penetrate the blood-brain barrier to bind with cannabinoid receptors present in the central nervous system (CNS). Nevertheless, there is still a distribution difference between CB1 (mainly in CNS) and CB2 (also covering peripheral tissues/organs, such as the pancreas and bone marrow)[1].

Metabolism and Excretion

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Most of the cannabinoid receptor modulators undergo phase I (oxidation, reduction, and hydrolysis) and/or phase II (conjugation) metabolism by hepatic CYP450 enzymes for the inactivation or detoxification of the modulators[15]. Their metabolites are excreted through the renal system (as urine) or the liver (as bile).

Drug-drug interaction[15]

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There is a potential for cannabinoid receptor modulators to have an interaction with the drugs which alter or rely on CYP450 enzyme metabolism. For example, cannabidiol is an inhibitor of CYP2C19 suggested by some clinical studies, meaning cannabidiol can increase the plasma concentration of the substrates of CYP2C19 such as clobazam to result in a drug overdose[23]. Besides, there are genetic polymorphisms among the cannabinoid receptors or the relevant drug-metabolizing enzymes such as CYP3A4 that contribute to the decision of dose adjustment or therapeutic drug monitoring for healthcare providers[24].      

Pharmacophores and their Structure-Activity Relationship (SAR)

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Scientists and/or researchers have been attempting to study the structural features of cannabinoid receptor modulator molecules to identify the key pharmacophores and establish corresponding SAR profiles which can assist relevant drug design and development. Some of the representative pharmacophores and their SAR are shown below illustration:

Δ9-THC

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(Main Article: THC)

Figure 5: SAR summary of Δ9-THC[25]

Most of the CB agonist derivatives are designed based on the SAR of Δ9-THC. The binding selectivity of the agonist can be achieved by modifying the C3 aliphatic side chain or the C1 hydroxy group.

Rimonabant

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Figure 6: Structural interaction of rimonabant with CB1[26]

Rimonabant is the first CB1 inverse agonist whose molecular structure represents the common features of most CB1 inverse antagonists. Principally, CB1 inverse agonists consist of two aromatic rings unilaterally attaching to the central ring core (either heterocyclic or aromatic), a hydrogen bond acceptor group (usually carbonyl group) inserted next to the ring core, and a lipophilic moiety such as piperidine ring substituted next to the hydrogen bond acceptor group[26].  

Some representative pharmacophores of CB1 allosteric modulators

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Indole-2-carboxamides

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Figure 7: Schematic summary of indole-2-carboxamides SAR[21]

Diaryl ureas

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Figure 8: Schematic summary of diaryl ureas SAR[21]

2-phenyl indoles

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Figure 9: Schematic summary of 2-phenyl indoles SAR[21]
Figure 10: A gram-scale synthesis route for 2-phenyl indoles[27]
Synthesis
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The 2-phenyl indole type of CB1 allosteric modulators can be synthesized through the reaction mechanism of Michael addition by reacting 2-phenyl indole derivatives with the derivatives of β-nitrostyrene under microwave conditions[27].  

Medical uses

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Cannabinoid agonists — Chronic pain

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The potential use of cannabinoid agonists, mostly THC and CBD derived from whole-plant cannabis, extracted from cannabis, or synthesized synthetically, for treating chronic pain of various causes has been extensively studied. However, meta-analyses and reviews either demonstrated weak evidence of its efficacy[28][29][30], potential benefits outweighed by the risks of treatment[28][30][31][32] or lack of clinical significance compared to placebo or standard treatment[28][31]. While pure THC or extracts with a high THC content are supported by more evidence for its use in cancer pain[28] and neuropathic pain, CBD is not found to be efficacious[29][30][32]. However, a high concentration of THC is also associated with an increased occurrence of adverse reactions, thus clinical use is limited[28][30][32]. Even though cannabis products can be legally prescribed for the indication of chronic pain being available legally in certain areas of the US[33], UK[34] and EU[35], official guidelines of all three regions recommend against the use of THC and CBD for chronic pain due to mixed evidence, and especially the associated risks from adverse reactions and potential addiction caused by THC or other cannabinoids present in such products[35][36][37].

Cannabinoid agonists — Chemotherapy-induced nausea and vomiting (CINV)

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Both dronabinol and nabilone (which are synthetic forms of THC) for the indication of CINV prophylaxis were approved by FDA in 1985, due to the lack of effective treatment back in the time[38]. The two cannabinoids demonstrate tolerable adverse effect profiles and favourable risk-to-benefit ratios in terms of safety based on current systematic reviews and meta-analyses[39][40]. However, due to insufficient evidence of efficacy compared to the current standard regimen, it is not considered a first-line treatment[41]. A systematic review found that past clinical studies and reviews had poor methodological quality, leading to unreliable results[42]. Another review supports this perspective by highlighting the experimental design of the analysed trials being below current standards, often using placebo or drugs used before the establishment of current standard treatment as the control group, thus results may be questionable or inconclusive[43]. Therefore, dronabinol and nabilone are currently only recommended to be used as an add-on drug for refractory or intractable CINV after the standard regimen is optimised, by NICE guidelines from the UK[37], ASCO guidelines from the US[44], and the international MASCC guideline[45].

Cannabinoid antagonists/inverse agonists

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Rimonabant is the first cannabinoid receptor inverse agonist studied for human use[46]. The discovery of its effect in modulating lipogenesis and adipogenesis triggered research into its application in treating obesity which results from clinical trials had shown its effect to be promising[46][47]. The protective effect of inhibiting peripheral CB1 receptors on pancreatic β-cells was utilised to treat diabetes mellitus, which also showed a substantial effect on slowing progression in trials[46][48]. Another property of rimonabant is modulation of the reward pathway in the brain[46][49][50], which has shown improved abstinence in both smoking cessation[49][51] and alcoholism treatment[50]. However, due to its penetration through the blood-brain barrier and binding to central CB1 receptors, later revealed that it can cause serious psychiatric adverse effects including anxiety, depression and suicidal ideation and was withdrawn from the market[46][52][53]. The development of a longer-acting second generation of the class is terminated shortly, including surinabant, ibipinabant, taranabant, and otenabant[46][53]. New research aims to achieve the same benefits of CB1 inhibition while avoiding adverse effects by increasing selectivity towards peripheral CB1 receptors through changes in binding mode, such as allosteric modulation, or by altering the drug's penetrability to the blood-brain barrier[46][48][53].

Adverse effects

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CBD is generally well-tolerated with mild adverse effects, including decreased appetite, somnolence, diarrhea and fatigue, agreed by several meta-analyses[54][55][56]. More serious adverse effects include pneumonia, sedation and abnormal liver function test result[54][56], yet the results produced may be caused by other comorbidities[54] and concomitant drug use[56].

THC is well known for its psychoactive properties and its related physiological effects. When THC is used in high doses, commonly in recreational use, it can induce psychosis-like symptoms, including positive psychotic symptoms, like hallucinations and delusions; negative symptoms like reduced emotions, interest and motivations; and other symptoms like depression and anxiety[huit]. At lower doses for medicinal use, THC can still induce central nervous system effects like hallucination, sedation, and euphoria but at a low prevalence[39]. Other common side effects are drowsiness, dizziness, dry mouth, fatigue, headache and nausea[39]. It can also cause serious cardiovascular adverse effects like myocardial infarction and stroke[39][57], as well as respiratory adverse effects like pneumonia[39].

Long-term adverse effects of both CBD and THC have been studied, although to a limited extent. For CBD, chronic effects include induced psychiatric effects (anxiety, depression, mania, hallucinations), impaired cognitive or attention (memory impairment and confusion) and increased risk of motor accidents[58]. As for THC, chronic effects include memory, motor, attention and learning impairment, psychosis and impulsivity[59]. Another rare adverse effect that is associated with general cannabinoid use is Cannabis Hyperemesis Syndrome, which is characterized by recurrent episodes of severe vomiting[60]. However, the CBD review deemed the findings to be imprecise, inconsistent and have a high risk of bias[58], while the other two suggest the need for further studies to confirm their findings[59][60].

History

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The discovery of the first cannabinoid receptor, CB1, occurred in the late 1980s during research on the effects of ​THC, the main​ psychoactive ​compound in cannabis​. The CB1 receptor was identified and cloned in 1990. ​A second cannabinoid receptor, CB2,​ was discovered in 1993[61].

The identification of cannabinoid receptors sparked interest in developing cannabinoid receptor modulators as potential therapies. Synthetic cannabinoids, such as nabilone and dronabinol, which are structurally similar to THC, were developed and approved for medical use in various countries. They have been used to alleviate chemotherapy-induced nausea and vomiting and stimulate appetite in HIV/AIDS patients[61].

Researchers later focused on developing selective modulators that target specific cannabinoid receptors. This led to the discovery of compounds that selectively activate CB1 or CB2 receptors, opening up new possibilities for therapeutic applications. Selective CB2 agonists have shown promise in managing inflammatory and autoimmune conditions, while selective CB1 antagonists have been investigated for treating obesity and addiction[61].

Relevant legislation

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Mainland China

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Cannabis is classified as a narcotic drug and a Class I psychotropic substance in China, subject to strict control measures. According to Article 357 of China's Criminal Law, the List of Narcotic Drugs (2013 Edition), and the List of Psychotropic Drugs (2013 Edition), cannabis, cannabis resin, cannabis extracts, tinctures, and tetrahydrocannabinol (THC) are categorized as drugs[62]. Smuggling, selling, transporting, or manufacturing drugs, regardless of quantity, is considered a criminal offense under Article 347, with the maximum penalty being the death sentence[62]. Illegally possessing a "large" or "relatively large" amount of drugs is punishable by detention, public surveillance, fixed-term imprisonment, or life imprisonment, as stated in Article 348[62]. The Supreme People's Court interpretation on drug cases specifies that a "relatively large" amount of cannabis refers to 1 to 5 kg of cannabis oil, 2 to 10 kg of cannabis resin, or 30 to 150 kg of cannabis leaves and cigarettes[62]. Infringing upon Article 72 and 73 of the Law on Penalties for Administration of Public Security, which prohibit the ingestion, possession, provision, instigation, induction, or deception of others related to drugs, can result in up to 15 days of detention or a fine of up to RMB 2,000[62]. The Regulations on the Control of Narcotic Drugs and Psychotropic Drugs mandate state control over narcotic drug source plants, narcotic drugs, and psychotropic drugs, prohibiting any activities involving their cultivation, research, production, operation, use, storage, or transportation, unless specifically authorized[7]. The List of Narcotic Drugs includes cannabis, even though it is not produced or used in China.

United Kingdom

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The United Kingdom does not impose legal restrictions on the indications for which cannabis-based medicinal products (CBPMs) can be prescribed. The decision to prescribe CBPMs is based on clinical judgment, taking into account factors such as the patient's values, clinical condition, and the suitability of other licensed medicines[6]. CBPMs have the most evidence of clinical effectiveness in treating intractable nausea and vomiting, multiple sclerosis-related spasticity, and severe treatment-resistant epilepsy[63]. However, they are not typically considered as the first-line treatment options since most CBPMs are unlicensed. Licensed medicines for the specific condition should be prioritized by prescribers.

To qualify as a cannabis-based medicinal product (CBPM), a product must meet three requirements[6]:

  1. It must contain cannabis, cannabis resin, cannabinol, or a cannabinol derivative.
  2. It must be produced for medicinal use in humans.
  3. It must be regulated as a medicinal product or an ingredient of one.

United States

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Cannabis is classified as a Schedule I controlled substance under federal law in the United States, making it illegal at the federal level[64]. However, several states have legalized cannabis for medical and/or recreational purposes, resulting in a complex legal landscape[5]. The FDA has approved a few medicinal drugs containing cannabinoids such as THC and CBD[65]. At the federal level, cannabis remains a Schedule I substance under the Controlled Substances Act, because it "has a high potential for abuse"[64] and "has no currently accepted medical use"[64][65]. However, in accordance with state laws during 2009, federal prosecutors received a guidance from the Obama Administration, which issued not to prosecute individuals distributing cannabis for medical purposes[65][66]. In 2013, the U.S. Department of Justice announced that it would defer to state-based enforcement efforts in states like Colorado and Washington, while maintaining the right to challenge their legalization laws if necessary. However, in 2018, the Cole Memorandum, which provided guidance on federal enforcement of cannabis laws, was rescinded[65]. This change allowed federal prosecutors to selectively prosecute based on factors such as "federal law enforcement priorities set by the Attorney General, the seriousness of the crime, the deterrent effect of criminal prosecution, and the cumulative impact of particular crimes on the community"[65][67].

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