Novel Cannabinoid Receptor Ligands: Discovery, Pharmacology, and Therapeutic Applications

A Special Issue of Pharmaceuticals (ISSN 1424-8247) belonging to the section "Pharmacology".

Deadline for manuscript submissions: 31 October 2026 | Viewed by 691

Editors


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Guest Editor
Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy
Interests: annabinoid research; allosteric/bitopic modulation; isotope-labeled compounds; imaging agents

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Guest Editor
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: cannabinoid research; allosteric/bitopic modulation; natural products; antioxidants; neurodegeneration
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Special Issue Information

Dear Colleagues,

Cannabinoids constitute a structurally diverse class of naturally occurring and synthetic compounds capable of modulating a wide range of cellular processes through specific cell-signaling pathways. They are commonly classified into three main categories: endogenous cannabinoids (endocannabinoids), phytocannabinoids, and synthetic cannabinoids. Their biological effects primarily arise from interaction with cannabinoid receptors expressed on the cell surface. Cannabinoid receptors belong to the superfamily of G protein-coupled receptors (GPCRs), one of the largest and most versatile classes of signaling proteins. Cannabinoids are known to interact predominantly with two receptor subtypes, namely cannabinoid receptor type 1 (CB1) and type 2 (CB2), whose activation or modulation triggers distinct intracellular signaling cascades regulating numerous physiological and pathological processes.

Growing interest in the therapeutic potential of cannabinoids has emerged from their involvement in a wide spectrum of diseases and conditions, including cancer, neurodegenerative disorders, inflammation, autoimmune diseases, and other unmet medical needs. Consequently, cannabinoid receptor ligands represent highly attractive molecular templates for modern drug discovery. Nevertheless, significant challenges remain, including the identification of novel ligands with improved receptor selectivity, optimized signaling profiles, and enhanced safety margins.

Despite the limited number of cannabinoid-based drugs currently approved for clinical use, numerous candidates are under preclinical and clinical investigation, highlighting the largely untapped potential of cannabinoid receptor modulation.

This Special Issue of Pharmaceuticals welcomes both original research articles and comprehensive reviews focusing on recent advances in the medicinal chemistry and pharmacology of cannabinoid receptor ligands. The scope of this Special Issue will include classical and next-generation cannabinoid ligands, including allosteric modulators, biased and covalent ligands, proteolysis targeting chimeras (PROTACs), and labeled chemical probes, to gain further insights into cannabinoid receptor function and dynamics and to unlock their potential in medicine.

Dr. Rebecca Ferrisi
Dr. Clementina Manera
Guest Editors

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Keywords

  • cannabinoid receptor modulators
  • synthetic cannabinoids
  • allosteric modulation
  • biased signaling
  • covalent ligands
  • PROTACs
  • cannabinoid probes
  • inflammation
  • CNS disorders
  • cancer

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Published Papers (1 paper)

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Research

19 pages, 2480 KB  
Article
Neurotoxicity of Synthetic Cannabinoid Receptor Agonist Cumyl-PINACA: An In Vitro Study on Rat Cortical Neurons and Astrocytes
by Damijana Mojca Jurič, Klara Bulc Rozman, Metoda Lipnik-Štangelj, Dušan Šuput and Miran Brvar
Pharmaceuticals 2026, 19(9), 1436; https://doi.org/10.3390/ph19091436 - 10 Sep 2026
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Abstract
Background/Objectives: Synthetic cannabinoid receptor agonists (SCRAs) are associated with severe neurotoxicity, but the cellular mechanisms underlying their effects remain poorly defined. We investigated the effects of Cumyl-PINACA (SGT-24), a carboxamide-type SCRA derived from cumylamine, on rat cortical neurons and astrocytes. Methods: Primary rat [...] Read more.
Background/Objectives: Synthetic cannabinoid receptor agonists (SCRAs) are associated with severe neurotoxicity, but the cellular mechanisms underlying their effects remain poorly defined. We investigated the effects of Cumyl-PINACA (SGT-24), a carboxamide-type SCRA derived from cumylamine, on rat cortical neurons and astrocytes. Methods: Primary rat cortical neurons and astrocytes were exposed to 1–10,000 nM SGT-24. Metabolic activity, mitochondrial function, morphology, and cell death were evaluated. Selective antagonists of cannabinoid receptor type 1 (CB1), G protein-coupled receptor 55 (GPR55), peroxisome proliferator-activated receptor gamma (PPARγ), and transient receptor potential cation channel subfamily V member 1 (TRPV1) were used to probe the involvement of these receptor pathways. Results: SGT-24 decreased metabolic activity in both cell types in a concentration- and time-dependent manner, with greater potency in neurons (IC50 = 13.2 nM) than in astrocytes (IC50 = 39.8 nM). After 24 h, maximal effects were observed at 100 nM in neurons and 500 nM in astrocytes, reducing metabolic activity by 45.2% and 36.2%, respectively. At these concentrations, mitochondrial membrane potential decreased to 57.6% and 54.1% of control, while cellular ATP levels fell to 51.6% and 52.5%, respectively. Neurons predominantly exhibited early apoptosis (21.9% of cells vs. 3.1% in controls), whereas astrocytes showed mainly 7-aminoactinomycin D (7-AAD)-positive cell death (19.3% vs. 8.2% in controls). Pharmacological inhibition of CB1, TRPV1, and PPARγ attenuated SGT-24-induced metabolic impairment, mitochondrial dysfunction, and apoptosis in neurons, whereas inhibition of CB1 and PPARγ reduced astrocytic toxicity. Conclusions: SGT-24 exerts potent, cell-type-dependent neuroglial toxicity associated with mitochondrial dysfunction and distinct cell death patterns, suggesting the involvement of cannabinoid receptor-dependent and non-cannabinoid signalling mechanisms. The nanomolar potency of SGT-24 underscores the toxicological risk posed by high-potency SCRAs. Full article
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