Preclinical Pharmacological and Brain Bioassay Systems for CB1 Cannabinoid Receptors

Pain is a complex multidimensional concept that facilitates the initiation of the signaling cascade in response to any noxious stimuli. Action potential generation in the peripheral nociceptor terminal and its transmission through various types of nociceptors corresponding to mechanical, chemical or thermal stimuli lead to the activation of receptors and further neuronal processing produces the sensation of pain. Numerous types of receptors are activated in pain sensation which vary in their signaling pathway. These signaling pathways can be regarded as a site for modulation of pain by targeting the pain transduction molecules to produce analgesia. On the basis of their anatomic location, transient receptor potential ion channels (TRPV1, TRPV2 and TRPM8), Piezo 2, acid-sensing ion channels (ASICs), purinergic (P2X and P2Y), bradykinin (B1 and B2), α-amino-3-hydroxy-5- methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), metabotropic glutamate (mGlu), neurokinin 1 (NK1) and calcitonin gene-related peptide (CGRP) receptors are activated during pain sensitization. Various inhibitors of TRPV1, TRPV2, TRPM8, Piezo 2, ASICs, P2X, P2Y, B1, B2, AMPA, NMDA, mGlu, NK1 and CGRP receptors have shown high therapeutic value in experimental models of pain. Similarly, local inhibitory regulation by the activation of opioid, adrenergic, serotonergic and cannabinoid receptors has shown analgesic properties by modulating the central and peripheral perception of painful stimuli. This review mainly focused on various classes of nociceptors involved in pain transduction, transmission and modulation, site of action of the nociceptors in modulating pain transmission pathways and the drugs (both clinical and preclinical data, relevant to targets) alleviating the painful stimuli by exploiting nociceptor-specific channels and receptors.

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Emerging Biomarkers and Contributing Factors of Prostate Cancer.

Current Cancer Therapy Reviews ◽

10.2174/1573394716999201016155640 ◽

2020 ◽

Vol 16 ◽

Author(s):

Mini Dahiya ◽

Monu Yadav ◽

Kalpana Nagpal ◽

Nidhi Sharma ◽

Kajal Joshi ◽

...

Keyword(s):

Oxidative Stress ◽

Prostate Cancer ◽

Tumor Suppressor Genes ◽

Therapeutic Strategy ◽

Cannabinoid Receptors ◽

Contributing Factors ◽

Cause Of Deaths ◽

Pharmaceutical Industries ◽

Brca1 Brca2 ◽

Molecular Pathophysiology

: Prostate Cancer (PC) is one the most prominent cause of deaths in males worldwide especially in western countries. The exhaustive research into prostate cancer to date has demonstrated ELAC2, RNASEL, MSR1, NBS1, CHEK2, MYC, BCL-2, c-Kit, tumor suppressor genes, BRCA1, BRCA2, PACE4, GSTP1, PTEN,CDKN1B, NKX3.1, KLF6, FOXA1, Retinoblastoma, p53, androgen receptor, kallikreins, ETS, CYP17, SRD5A2, E-cadherin, KAI1/CD82, hepsin, AMACR, PIM1, MTA-1, EZH2, EPHB2, growth factors & its receptors, cannabinoid receptors, annexins, oxidative stress and inflammation are entailed changes underlying the initiation, development, and progression of PC. Furthermore, oncology would shift from a reactive to proactive discipline so exploring these targets open new area of research. Therefore, the present review is focused on molecular pathophysiology biomarkers for the progression of PC that would encourage the researchers and pharmaceutical industries to investigate potential therapeutic strategy to overcome demerits of currently available clinically therapies.

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Molecular Modeling of an Orphan GPR18 Receptor

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180810114847 ◽

2019 ◽

Vol 16 (10) ◽

pp. 1167-1174 ◽

Cited By ~ 2

Author(s):

Kamil J. Kuder ◽

Tadeusz Karcz ◽

Maria Kaleta ◽

Katarzyna Kiec-Kononowicz

Keyword(s):

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Glycine Receptor ◽

Homology Model ◽

Orphan Receptor ◽

Receptor Ligands ◽

Orphan Receptors ◽

Inactive Form ◽

Starting Point ◽

Endogenous Cannabinoid

Background: : One of the best known to date GPCR class A (Rhodopsin) includes more than 100 orphan receptors for which the endogenous ligand is not known or is unclear. One of them is N-arachidonyl glycine receptor, named GPR18, a receptor that has been reported to be activated by Δ9-THC, endogenous cannabinoid receptors agonist anandamide and other cannabinoid receptor ligands suggesting it could be considered as third cannabinoid receptor. GPR18 activity, as well as its distribution might suggest usage of GPR18 ligands in treatment of endometriosis, cancer, and neurodegenerative disorders. Yet, so far only few GPR18 antagonists have been described, thus only ligand-based design approaches appear to be most useful to identify new ligands for this orphan receptor. Methods: : Main goal of this study, GPR18 inactive form homology model was built on the basis of the evolutionary closest homologous template: Human P2Y1 Receptor crystal structure. Results: : Obtained model was further evaluated and showed active/nonactive ligands differentiating properties with acceptable confidence. Moreover, it allowed for preliminary assessment of proteinligand interactions for a set of previously described ligands. Conclusion:: Thus collected data might serve as a starting point for a discovery of novel, active GPR18 blocking ligands.

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Endocannabinoid System Dysregulation from Acetaminophen Use May Lead to Autism Spectrum Disorder: Could Cannabinoid Treatment Be Efficacious?

Molecules ◽

10.3390/molecules26071845 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1845

Author(s):

Stephen Schultz ◽

Georgianna G. Gould ◽

Nicola Antonucci ◽

Anna Lisa Brigida ◽

Dario Siniscalco

Keyword(s):

Autism Spectrum Disorder ◽

Cannabinoid Receptors ◽

Current Knowledge ◽

Endocannabinoid System ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Blood Levels ◽

Increased Risk ◽

Patterns Of Behavior ◽

Arachidonoyl Glycerol

Persistent deficits in social communication and interaction, and restricted, repetitive patterns of behavior, interests or activities, are the core items characterizing autism spectrum disorder (ASD). Strong inflammation states have been reported to be associated with ASD. The endocannabinoid system (ECS) may be involved in ASD pathophysiology. This complex network of lipid signaling pathways comprises arachidonic acid and 2-arachidonoyl glycerol-derived compounds, their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. Alterations of the ECS have been reported in both the brain and the immune system of ASD subjects. ASD children show low EC tone as indicated by low blood levels of endocannabinoids. Acetaminophen use has been reported to be associated with an increased risk of ASD. This drug can act through the ECS to produce analgesia. It may be that acetaminophen use in children increases the risk for ASD by interfering with the ECS.This mini-review article summarizes the current knowledge on this topic.

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