scholarly journals Positive Allosteric Modulation of CB1 and CB2 Cannabinoid Receptors Enhances the Neuroprotective Activity of a Dual CB1R/CB2R Orthosteric Agonist

Life ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 333
Author(s):  
Beatrice Polini ◽  
Chiara Cervetto ◽  
Sara Carpi ◽  
Simone Pelassa ◽  
Francesca Gado ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Cannabinoid Receptors ◽  
Glutamate Release ◽  
Neuroprotective Activity ◽  
Allosteric Modulators ◽  
Therapeutic Benefits ◽  
Promising Therapeutic Approach ◽  
Excitotoxic Damage ◽  
Positive Allosteric Modulators ◽  
Chronic Use

Preclinical studies highlighted that compounds targeting cannabinoid receptors could be useful for developing novel therapies against neurodegenerative disorders. However, the chronic use of orthosteric agonists alone has several disadvantages, limiting their usefulness as clinically relevant drugs. Positive allosteric modulators might represent a promising approach to achieve the potential therapeutic benefits of orthosteric agonists of cannabinoid receptors through increasing their activity and limiting their adverse effects. The aim of the present study was to show the effects of positive allosteric ligands of cannabinoid receptors on the activity of a potent dual orthosteric agonist for neuroinflammation and excitotoxic damage by excessive glutamate release. The results indicate that the combination of an orthosteric agonist with positive allosteric modulators could represent a promising therapeutic approach to the treatment of neurodegenerative disorders.

scholarly journals Allosteric modulators targeting cannabinoid cb1 and cb2 receptors: implications for drug discovery

2019 ◽  
Vol 11 (15) ◽  
pp. 2019-2037 ◽  
Author(s):  
Francesca Gado ◽  
Serena Meini ◽  
Simone Bertini ◽  
Maria Digiacomo ◽  
Marco Macchia ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Allosteric Modulators ◽  
Cb2 Receptor ◽  
Pharmacological Profile ◽  
Therapeutic Benefits ◽  
Structure Activity ◽  
Biased Signaling ◽  
Orthosteric Ligands

Allosteric modulators of cannabinoid receptors hold great therapeutic potential, as they do not possess intrinsic efficacy, but instead enhance or diminish the receptor's response of orthosteric ligands allowing for the tempering of cannabinoid receptor signaling without the desensitization, tolerance and dependence. Allosteric modulators of cannabinoid receptors have numerous advantages over the orthosteric ligands such as higher receptor type selectivity, probe dependence and biased signaling, so they have a great potential to separate the therapeutic benefits from side effects own of orthosteric ligands. This review aims to give an overview of the CB1 and CB2 receptor allosteric modulators highlighting the structure–activity relationship and pharmacological profile of each classes, and their future promise.

Application of Monoterpenoids and their Derivatives for Treatment of Neurodegenerative Disorders

2019 ◽  
Vol 25 (39) ◽  
pp. 5327-5346 ◽  
Author(s):  
Konstantin P. Volcho ◽  
Sergey S. Laev ◽  
Ghulam Md Ashraf ◽  
Gjumrakch Aliev ◽  
Nariman F. Salakhutdinov
Keyword(s):  
Alzheimer’S Disease ◽  
Clinical Trials ◽  
Huntington's Disease ◽  
Neurodegenerative Disorders ◽  
Heterogeneous Group ◽  
Neuroprotective Activity ◽  
Severe Loss ◽  
Neurotrophic Activity ◽  
Full Proof ◽  
Effective Treatments

Neurodegenerative disorders (NDDs) like Alzheimer's disease, Parkinson’s disease and Huntington’s disease are a heterogeneous group of disorders with the progressive and severe loss of neurons. There are no full proof cures for these diseases, and only medicines are available that can alleviate some of the symptoms. Developing effective treatments for the NDDs is a difficult but necessary task. Hence, the investigation of monoterpenoids which modulate targets applicable to many NDDs is highly relevant. Many monoterpenoids have demonstrated promising neuroprotective activity mediated by various systems. It can form the basis for elaboration of agents which will be useful both for the alleviation of symptoms of NDDs and for the treatment of diseases progression and also for prevention of neurodegeneration. The further developments including detections of monoterpenoids and their derivatives with high neuroprotective or neurotrophic activity as well as the results of qualified clinical trials are needed to draw solid conclusions regarding the efficacy of these agents.

scholarly journals Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models

2013 ◽  
Vol 65 ◽  
pp. 156-164 ◽  
Author(s):  
Kelen Freitas ◽  
Sudeshna Ghosh ◽  
F. Ivy Carroll ◽  
Aron H. Lichtman ◽  
M. Imad Damaj
Keyword(s):  
Neuropathic Pain ◽  
Allosteric Modulators ◽  
Chronic Neuropathic Pain ◽  
Pain Models ◽  
Positive Allosteric Modulators ◽  
Alpha 7

scholarly journals Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators

2021 ◽  
Vol 22 (2) ◽  
pp. 973
Author(s):  
Marta Ximenis ◽  
José Mulet ◽  
Salvador Sala ◽  
Francisco Sala ◽  
Manuel Criado ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Allosteric Modulators ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Curcumin Analogues ◽  
Curcumin Derivatives ◽  
Curcumin Analogs ◽  
Naturally Occurring ◽  
Α7 Nachr ◽  
Positive Allosteric Modulators ◽  
Α7 Nachrs

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of α7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the α7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of α7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh; the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising.

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