CB1 allosteric modulators and their therapeutic potential in CNS disorders
Section snippets
Cannabinoid receptor 1 (CB1)
CB1 was first characterized by Δ9-tetrahydrocannabinol (THC)-specific Gαi signaling that results in a decrease in cellular cAMP levels (Howlett et al., 1988, Howlett et al., 1986). This receptor was subsequently cloned and named CB1, a 472 residue Gαi coupled G protein-coupled receptor (GPCR; Gérard et al., 1990; Matsuda et al., 1990). The cannabinoid receptor 2 (CB2) was later discovered, and together with CB1, they comprise the cannabinoid family of GPCRs (Munro et al., 1993).
Localization
Background: Allosterism summary
The study of allosterism is a relatively new concept in the field of GPCR research. While the concept was elucidated many years ago for other proteins, such as enzymes or ion channels, concrete evidence of GPCR allosterism did not arise until the early 1990s. The first published observation of allosteric modulation of a GPCR was revealed when several compounds were found to non-competitively block agonist-induced signaling of the α2- and β2-adrenergic receptors, without signaling profiles on
Targeting CB1 via allosteric modulation
As one of the most abundant GPCRs found in the mammalian brain, it is understandable that CB1 has garnered considerable attention as a potential therapeutic drug target. Considering its involvement in a wide range of physiological and psychiatric processes, including the regulation of pain, appetite, learning and memory, anxiety, and depression (Nguyen et al., 2019c, Nguyen et al., 2017b), CB1 is a potential therapeutic target in several disease states. Most of the selective and non-selective
Negative allosteric modulators (NAMs)
The in vitro effects of CB1 NAMs have been reviewed elsewhere (Dopart et al., 2018; Khurana et al., 2017b; Nguyen et al., 2017c). Here, we summarize the in vitro effects, specifically of NAMs, that have been characterized in vivo. Details summarized in Table 1.
In vivo pre-clinical studies of cb1 allosteric modulators
To assess in vivo effects of pharmacological compounds targeting the central CB1 receptor in rodent models, the pre-clinical model most commonly used is the cannabinoid-induced tetrad (referred to as the tetrad). The tetrad is characterized by hypolocomotion, hypothermia, catalepsy and antinociception (Metna-Laurent et al., 2017). First demonstrated by the prototypic phytocannabinoid THC (Compton et al., 1992; Martin et al., 1991), these four phenotypes are induced in rodents following acute
CB2 allosteric modulation and CNS disorders
Since its discovery in the late 1980’s, considerable work has been done investigating the therapeutic potential of CB1 in treating CNS disorders. It was commonly understood that CB1 was extensively expressed in the CNS, while CB2 was peripherally restricted to the immune system, presumed absent from the CNS (Atwood and MacKie, 2010). However, despite high expectations for CB1-targeting drugs to treat disease states, following the removal of the first centrally-acting CB1 antagonist/inverse
Challenges in the validation of CB1 allosteric modulators
Thus far we have reviewed the published data for allosteric modulators and their potential efficacy in vivo. The challenges associated with the study of allosteric modulators in vivo can be separated into the following five categories:
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In Vivo Model Chosen: As with all in vivo studies, the model and strain used to validate in vivo effects is integral to the interpretation and confirmation of results. In the studies highlighted in Table 3, Table 4, it is evident that there is little consistency
Future directions
Future experiments should expand validation of CB1 allosteric modulators to a broader number of psychiatric disorders and behavioural domains, while including both males and females. Focus could be given to the role of CB1 PAMs in the treatment of anxiety and depression, as current investigations of this therapeutic avenue are few (Khurana et al., 2017b), despite evidence that the ECS is an integral regulator of stress response (Morena et al., 2016). Exploration of CB1 NAMs and their
Declaration of Competing Interest
The authors declare the following financial and biomedical conflict of interest: Ruth A. Ross and Catharine A. Mielnik are co-inventors on a patent application related to ABM300 and structural analogues.
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2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryThe synthetic CB<inf>1</inf> cannabinoid receptor selective agonists: Putative medical uses and their legalization
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :The synthetic cannabinoid receptor selective agonists represent a collection of diverse compounds that exhibit high affinity binding to the CB1/CB2 cannabinoid receptors and display a pharmacological profile similar to Δ9-THC (Brunt and Bossong, 2020; Potts et al., 2020; Walsh and Andersen, 2020a, 2020b; Patel et al., 2021). Given that there are more than 100 compounds belonging to the synthetic cannabinoid receptor selective agonists (Morales et al., 2016; Brunt and Bossong, 2020; Potts et al., 2020; Sholler et al., 2020; Stasiulewicz et al., 2020; Mielnik et al., 2021), it is indeed ambitious to summarize all current evidence. However, we provide a brief overview of the major CB1 cannabinoid receptor selective agonists studied, and we then discuss the side effects associated with these compounds and their legal status and safety concerns.
The endocannabinoidome in neuropsychiatry: Opportunities and potential risks
2021, Pharmacological ResearchCitation Excerpt :However, historical evidence suggests that the pharmacological manipulation of CB1R expression and/or levels is not without hazards. Agonism or inverse agonism of CB1Rs have been associated with serious psychiatric adverse effects, such as psychosis and/or panic attacks, whilst antagonism to those receptors would arguably impair CNS homeostasis [82–85]. CB2Rs appear to be most prevalent on postsynaptic somatodendritic areas [86–88] and the activation of postsynaptic CB2Rs usually inhibits neuronal excitability [89,90].
Pharmacological selection of cannabinoid receptor effectors: Signalling, allosteric modulation and bias
2021, NeuropharmacologyCitation Excerpt :The mechanism for this was not described, but it does suggest that there may be cell specific factors required for this signalling, such as different CB1 expression levels in different neurons (Mitjavila et al., 2018). Subsequent to the initial discovery of these allosteric ligands, a number of studies have been published testing these in a range of CNS disease models with promising results – this data has been recently reviewed (Mielnik et al., 2021a). In summary, there is good evidence to suggest that ZCZ-011, GAT229, and the CF3-substituted analogue of ZCZ-011 are promising lead molecules in the search for therapeutically useful positive allosteric modulators of CB1.
Effects of the cannabinoid receptor 1 positive allosteric modulator GAT211 and acute MK-801 on visual attention and impulsivity in rats assessed using the five-choice serial reaction time task
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :For example, CBD has been found to inhibit the reuptake of AEA, and the concentration of AEA in the cerebrospinal fluid is found to be inversely related to the severity of psychosis symptoms in schizophrenia patients (Manseau and Goff, 2015; Giuffrida et al., 2004). Therefore, there is merit in studying the modulation of CB1R in the context of schizophrenia (Mielnik et al., 2020). A positive allosteric modulator (PAM) is a ligand that binds to a site on its receptor that is distinct from the main (i.e., orthosteric) site of endogenous binding and in doing so enhances the potency of the orthosteric ligand and/or the efficacy of the receptor's signaling (Laprairie et al., 2017).
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Both equally contributed.