Abstract
The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid tolerance development, and abuse potential. Ligands that produce biased signaling—the preferential activation of a signaling transducer in detriment of another—have been proposed as a strategy to dissociate therapeutic and adverse effects for a variety of G-protein coupled receptors. However, biased signaling at the CB1 receptor is poorly understood due to a lack of strongly biased agonists. Here, we review studies that have investigated the biased signaling profile of classical cannabinoid agonists and allosteric ligands, searching for a potential therapeutic advantage of CB1 biased signaling in different pathological states. Agonist and antagonist bound structures of CB1 and proposed mechanisms of action of biased allosteric modulators are used to discuss a putative molecular mechanism for CB1 receptor activation and biased signaling. Current studies suggest that allosteric binding sites on CB1 can be explored to yield biased ligands that favor or hinder conformational changes important for biased signaling.
Highlights
The cannabinoid receptor type 1 (CB1) is a class A G-protein coupled receptor (GPCR) that was first discovered as the main target for ∆9-tetrahydrocannabinol (THC), the psychoactive compound in Cannabis
In accordance with Breivogel et al [112], this study found that β-arrestin2 KO increased antinociception and hypothermia in response to acute THC treatment; no difference was found in cannabinoid-induced G-protein activity in central nervous system (CNS) regions associated with antinociception, i.e., periaqueductal gray (PAG) and spinal cord, or hypothermia—the preoptic area of the hypothalamus
These findings indicate that β-arrestin2 regulates desensitization of CB1 induced G-protein activity in PAG, spinal cord, and preoptic area of the hypothalamus, and that desensitization by β-arrestin2 is the underlying mechanism behind the development of tolerance to cannabinoid antinociception and hypothermia
Summary
The cannabinoid receptor type 1 (CB1) is a class A G-protein coupled receptor (GPCR) that was first discovered as the main target for ∆9-tetrahydrocannabinol (THC), the psychoactive compound in Cannabis. Cannabinoid use is generally associated with cognitive impairment [23], a recent study showed that, while in young mice a chronic low dose THC treatment acts through CB1 to impair memory, it has the opposite effect in aged mice [24] This result, along with findings of reduced CB1 expression and function in aged mice [25] and of early onset cognitive dysfunction in mice with CB1 deletion [26], suggests that CB1 agonists may have a beneficial effect in the treatment of age-related cognitive impairment. The anxiolytic effect of cannabinoids, along with their negative modulation of hypothalamus–pituitary–adrenal axis activity mediated stress responses and facilitation of extinction learning in fear memory, led cannabinoid agonists to be investigated in the treatment of posttraumatic stress disorder (PTSD) In this context, positive results have been reported from CB1 and CB2 agonists in preclinical models [31], and a current phase 2 clinical study is underway to investigate the effect of Cannabis on symptoms of PTSD in war veterans (NCT02759185). CB1 agonists may mitigate HD progression and motor symptoms
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