Recent advances in the development of CB1R selective probes

Abstract

Cannabinoid subtype 1 receptors (CB1Rs) are an important class of G protein-coupled receptors (GPCRs) belonging to the endocannabinoid system. CB1Rs play a crucial modulatory role in the functioning of other neurotransmitter systems and are involved in a wide range of physiological functions and dysfunctions; thus, they are considered one of the most important targets for drug development, as well as diagnostic purposes. Despite this, only a few molecules targeting this receptor are available on the pharmaceutical market, thus emphasizing the need to gain a deeper understanding of the complex activation pathways of CB1Rs and how they regulate diseases. As part of this review, we provide an overview of pharmacological and imaging tools useful for detecting CB1Rs. Herein, we summarize the derivations of cannabinoids and terpenoids with fluorescent compounds, radiotracers, or photochromic motifs. CB1Rs’ molecular probes may be used in vitro and, in some cases, in vivo for investigating and exploring the roles of CB1Rs together with the starting point for the development of CB1R-targeted drugs.

Highly Selective Drug-Derived Fluorescent Probes for the Cannabinoid Receptor Type 1 (CB1R)

“…Fractions containing the product were combined and lyophilized to yield an orange powder (6.10 mg, 7.43 μmol, 49%). 1 (35). The Boc-protected amine (26) was dissolved in DCM (0.9 mL), and TFA (0.1 mL) was added.…”

“…Fluorescence-based techniques have evolved into a powerful method for studying G-protein coupled receptors (GPCRs). , In particular, small molecule fluorescent probes represent versatile tools to elucidate various mechanistic aspects of GPCR pharmacology. Among them are the detection of time-resolved target engagement, allosterism, internalization, dimerization, or membrane organization at the cellular level. − While several CB 2 R fluorescent probes were recently reported, only a few CB 1 R fluorescent probes have been described so far. , The only two examples of CB 1 R imaging probes are phytocannabinoid-derived ( 1 and 2 , Figure ). , In general, issues associated with phytocannabinoid probes are their limited selectivity over CB 2 R and lipophilicity that may result in a high unspecific background signal.…”

Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS

“…Therefore, there are several radioactively tagged agonist and antagonist ligands available for imaging with PET, autoradiography, or radioligand binding. For in vivo or ex vivo CB1R visualization, studies have mainly used PET imaging with [ 18 F]-or [ 11 C]-labelled ligands [53] (Table 3). For example, Burns et al were able to investigate the selective inverse agonist [ 18 F]MK-9470 both with PET and autoradiography, confirming its potential as an imaging tool for CB1R.…”

“…Fluorescence probes, however, allow real-time assessment with a high spatiotemporal precision and have been used in imaging studies. Their downside is that a link between the pharmacophore and the fluorescent tag is required as the probe affects various physicochemical and photophysical properties of the final conjugate [53]. An interesting application of fluorescent probes was found by Martin-Couce et al where a biotinylated 2-AGE analogue complex was successfully used to visualize CB1R in neurons [47].…”

Highly Selective Drug-Derived Fluorescent Probes for the Cannabinoid Receptor Type 1 (CB1R)

“…License: CC BY-NC-ND 4.0 reported, only a few CB1R fluorescent probes have been described so far. 34,35 The only two examples of CB1R imaging probes are phytocannabinoid-derived (1 and 2, Figure 1). 36,37 In general, issues associated with phytocannabinoid probes are their limited selectivity over CB2R and lipophilicity that may result in high unspecific background signal.…”