Cannabinoid receptor 2 (CB2) modulators: A patent review (2016-2024).

Cannabinoid receptors CB1 and CB2 play critical roles in regulating numerous central and peripheral physiological activities. While efforts have been made to develop ligands for both CB1 and CB2 receptors, CB1 receptor ligands often have restricted use due to undesirable psychotropic side effects. Consequently, recent cannabis research has increasingly focused on CB2-specific ligands. Pharmacological agonists of CB2 receptors have shown potential in managing pain, inflammation, arthritis, neuroprotection, cancer, and other disorders. Despite several CB2 receptor ligands entering clinical trials, none have achieved market approval except natural cannabinoids and their derivatives, primarily due to insufficient CB2/CB1 receptor selectivity. However, new-generation ligands developed in recent years have demonstrated improved selectivity. This review covers patent literature on CB2 modulators from 2016 to 2024, highlighting the major advances in the field. During this period, the majority of research has concentrated on using CB2 modulators to alleviate inflammation and pain. Additionally, patents have explored CB2 modulators for a range of specific diseases, including: psychiatric and neuropsychiatric disorders, schizophrenia, multiple myeloma and osteoporosis, ocular inflammation and neuropathic Pain, cancer anorexia and weight loss, antioxidant and anti-aging agents, lymphocytopenia, hearing loss, Alzheimer's disease, cancer and non-malignant tumors. Notably, recent years have seen increased interest in CB2 antagonists/inverse agonists, with few candidates advancing to clinical studies. Significant progress has been made in the synthesis and modulation of selective CB2 agonists and antagonists, paving the way for future developments in CB2 modulators. This review provides insights and prospects for the continued evolution of CB2-targeted therapies.

Green synthesized AgNPs as a probe for colorimetric detection of Hg (II) ions in aqueous medium and fluorescent imaging in liver cell lines and its antibacterial activity.

The present research aimed at green synthesis of Ag nanoparticles (AgNPs) based colorimetric sensor using persimmon leaf extract (PLE) for selective detection of mercuric ion (Hg2+). Optimization of reaction conditions viz. pH, concentration of PLE, time was done and further AgNPs were characterized using UV, IR, FE-SEM, EDX, XRD and TEM analysis. The developed AgNPs were evaluated for the selective colorimetric detection of Hg2+ in aqueous medium and fluorescence imaging of Hg2+ ions in liver cell lines. Later, the antibacterial activity of AgNPs was performed against S. aureus and E. coli. The findings of the study revealed that PLE mediated AgNPs exhibited notable limit of detection up to 0.1 ppb, high efficiency, and stability. The antibacterial study indicated that developed AgNPs has impressive bacterial inhibiting properties against the tested bacterial strains. In conclusion, developed biogenic AgNPs has high selectivity and notable sensitivity towards Hg2+ ions and may be used as key tool water remediation.

Synthesis and Evaluation of Natural and Unnatural Tetrahydrocannabiorcol for Its Potential Use in Neuropathologies.

(-)-trans-Δ9-Tetrahydrocannabinol (trans-(-)-Δ9-THC) has shown neuroprotective potential, but its medicinal benefits are not fully exploited due to the limitations of psychoactive properties. The lower homologues are non-psychoactive in nature but lack comprehensive scientific validation regarding neuroprotective potential. The present study describes the synthesis of non-psychoactive lower homologues of THC-type compounds and their neuroprotective potential. Both natural tetrahydro-cannabiorcol (trans-(-)-Δ9-THCO) and unnatural Δ9-tetrahydrocannabiorcol (trans-(+)-Δ9-THCO) were successfully synthesized starting from R-limonene and S-limonene, respectively, and investigated for neuroprotective potential in cellular models. The structures of both enantiomers were confirmed by NMR, HMBC, HQSC, NOESY, and COSY experiments. Results indicated that both enantiomers were nontoxic to the cells treated up to 50 µM. Neuroprotective properties of the enantiomers showed that treatments could significantly reverse the corticosterone-induced toxicity in SH-SY5Y cells and simultaneously cause elevated expression of brain-derived neurotrophic factor (BDNF). It was also observed that unnatural trans-(+)-Δ9-THCO displayed better activity than the natural enantiomer and can be further explored for its potential use in neuropathological ailments.

Chemistry and pharmacological aspects of furanoid cannabinoids and related compounds: Is furanoid cannabinoids open a new dimension towards the non-psychoactive cannabinoids?

Cannabinoids have emerged as compelling candidates for medicinal applications, notably following the recent approval of non-psychoactive cannabidiol (CBD) as a medicine. This endorsement has stimulated a growing interest in this class of compounds for drug discovery. Within the cannabis plant, a rich reservoir of over 125 compounds exists. Tetrahydrocannabinol (THC), a member of the dibenzopyran class, is widely recognized for its psychoactive effects. Conversely, the furanoid class, represented by cannabielsoin-type (CBE) and cannabifuran-type (CBF) compounds, has not been reported with psychoactivity and demonstrates a spectrum of pharmacological potential. The transition from the pyran structure of THC to the furan structure of CBE seems to mark a shift from psychoactive to non-psychoactive properties, but a comprehensive examination of other members in this class is essential for a complete understanding. Building on these observations, our thorough review delves into the subject, offering a comprehensive exploration of furanoid cannabinoids, covering aspects such as their biosynthesis, classification, synthesis, and medicinal potential. The aim of this review is to encourage and catalyze increased research focus in this promising area of cannabinoid exploration.

Scoparone chemical modification into semi-synthetic analogues featuring 3-substitution for their anti-inflammatory activity.

Natural products (NPs) continue to serve as a structural model for the development of new bioactive molecules and improve the process of identifying novel medicines. The biological effects of coumarins, one of the most researched compounds among NPs, are currently being thoroughly investigated. In the present investigation, we reported the synthesis of nineteen semi-synthetic 3-substituted scoparone analogues, followed by their characterization using analytical methods such as NMR, HPLC, and HRMS. All compounds screened for in vitro and in vivo study for their ability to reduce inflammation. The SAR study worked effectively for this particular scoparone 3-substitution, as compounds 3, 4, 9, 16, 18, and 20 displayed improved in vitro results for TNF-α than the parent molecule. Similarly, compounds 3, and 17 showed a higher percentage of IL-6 inhibition. Compounds 3, 4, and 12 have also been identified by in vivo studies as promising candidates with higher percent inhibition than the parent scoparone molecule. As evident from all in vitro and in vivo studies, compound 3 showed the most potent anti-inflammatory activity among all.

Selective Interactions of Al(III) with Plasmonic AgNPs by Colorimetric, Kinetic, and Thermodynamic Studies.

In this paper, we report a simple, novel, and highly selective plasmonic nanoparticles (NPs)-based colorimetric nanoprobe for the detection of Al(III) ions in aqueous solution. 5-Hydroxy indole-2-carboxylic acid (5H-I2CA) was utilized as a reducing as well as capping agent for the preparation of silver nanoparticles (5H-I2CA@AgNPs). The interaction between Al(III) and AgNPs was determined by UV-vis absorption spectroscopy, high-resolution transmission electron microscopy, Fourier transform infrared, X-ray photoelectron spectroscopy, and dynamic light scattering techniques. The absorption values (A 452-410) of the 5H-I2CA@AgNPs solution exhibited a linear correlation with Al(III) ion concentrations within the linear range of 0.1-50 nM. An outstanding selectivity toward Al(III) was demonstrated by the proposed nanoprobe in the presence of interfering cations. Kinetics was used to study the selectivity of nanoprobe, which indicated second-order kinetics, and the rate constant was very high. The activation energies of Al(III) were found to be the lowest compared to those of other interfering ions. The results of kinetics and thermodynamic study of Al(III) were compared to those of four other competing ions. The thermodynamic data reveal that the interaction best suited for Al(III) ion compared to other metal ions (Al(III) > Co(II) > Hg(II) > Cr(III) ≅ Cr(VI)). The lower detection limit of the proposed nanoprobe for Al(III) is 1 nM. The present method also holds practical applicability for real water samples.