CB1 allosteric modulators and their therapeutic potential in CNS disorders

https://doi.org/10.1016/j.pnpbp.2020.110163Get rights and content

Highlights

  • Novel strategies to target CB1 with emphasis on elimination of adverse effects.

  • CB1 allosteric modulators have potential to target with fewer side effects.

  • Characterization of the therapeutic potential of CB1 allosterics has been slow.

  • Difficulties include poor pharmacokinetics and complex pharmacology.

  • Elucidating effects in vivo in appropriate disease models is essential and ongoing.

Abstract

CB1 is the most abundant GPCR found in the mammalian brain. It has garnered considerable attention as a potential therapeutic drug target. CB1 is involved in a wide range of physiological and psychiatric processes and has the potential to be targeted in a wide range of disease states. However, most of the selective and non-selective synthetic CB1 agonists and antagonists/inverse agonists developed to date are primarily used as research tools. No novel synthetic cannabinoids are currently in the clinic for use in psychiatric illness; synthetic analogues of the phytocannabinoid THC are on the market to treat nausea and vomiting caused by cancer chemotherapy, along with off-label use for pain. Novel strategies are being explored to target CB1, but with emphasis on the elimination or mitigation of the potential psychiatric adverse effects that are observed by central agonism/antagonism of CB1. New pharmacological options are being pursued that may avoid these adverse effects while preserving the potential therapeutic benefits of CB1 modulation. Allosteric modulation of CB1 is one such approach. In this review, we will summarize and critically analyze both the in vitro characterization and in vivo validation of CB1 allosteric modulators developed to date, with a focus on CNS therapeutic effects.

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:

  • 1.

    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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