Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists

: Alcohol-use disorder (AUD) remains a major public health concern. In recent years, there has been a heightened interest in components of the endocannabinoid system for the treatment of AUD. Cannabinoid type 1 (CB1) receptors have been shown to modulate the rewarding effects of alcohol, reduce the abuse-related effects of alcohol, improve cognition, exhibit anti-inflammatory, and neuroprotective effects, which are all favorable properties of potential therapeutic candidates for the treatment of AUD. However, CB1 agonists have not been investigated for the treatment of AUD because they stimulate the motivational properties of alcohol, increase alcohol intake, and have the tendency to be abused. Preclinical data suggest significant potential for the use of CB1 antagonists to treat AUD; however, a clinical phase I/II trial with SR14716A (rimonabant), a CB1 receptor antagonist/inverse agonist showed that it produced serious neuropsychiatric adverse events such as anxiety, depression, and even suicidal ideation. This has redirected the field to focus on alternative components of the endocannabinoid system, including cannabinoid type 2 (CB2) receptor agonists as a potential therapeutic target for AUD. CB2 receptor agonists are of particular interest because they can modulate the reward pathway, reduce abuse-related effects of alcohol, reverse neuroinflammation, improve cognition, and exhibit anti-inflammatory and neuroprotective effects, without exhibiting the psychiatric side effects seen with CB1 antagonists. Accordingly, this article presents an overview of the studies reported in the literature that have investigated CB2 receptor agonists with regards to AUD and provides commentary as to whether this receptor is a worthy target for continued investigation.

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Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists

Molecules ◽

10.3390/molecules23102630 ◽

2018 ◽

Vol 23 (10) ◽

pp. 2630 ◽

Cited By ~ 5

Author(s):

Pankaj Pandey ◽

Kuldeep Roy ◽

Haining Liu ◽

Guoyi Ma ◽

Sara Pettaway ◽

...

Keyword(s):

Natural Products ◽

Natural Product ◽

Binding Affinity ◽

Cannabinoid Receptor ◽

New Drugs ◽

In Vitro Screening ◽

Cannabinoid Receptor 1 ◽

Cardiometabolic Disorders ◽

Cb1 Antagonists

Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands. Cannabinoid receptor 1 (CB1) antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects. We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics. In search of new chemotypes as CB1 antagonists, we screened the in silico purchasable natural products subset of the ZINC12 database against our reported CB1 receptor model using the structure-based virtual screening (SBVS) approach. A total of 18 out of 192 top-scoring virtual hits, selected based on structural diversity and key protein–ligand interactions, were purchased and subjected to in vitro screening in competitive radioligand binding assays. The in vitro screening yielded seven compounds exhibiting >50% displacement at 10 μM concentration, and further binding affinity (Ki and IC50) and functional data revealed compound 16 as a potent and selective CB1 inverse agonist (Ki = 121 nM and EC50 = 128 nM) while three other compounds—2, 12, and 18—were potent but nonselective CB1 ligands with low micromolar binding affinity (Ki). In order to explore the structure–activity relationship for compound 16, we further purchased compounds with >80% similarity to compound 16, screened them for CB1 and CB2 activities, and found two potent compounds with sub-micromolar activities. Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands.

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Reports of the death of CB1 antagonists have been greatly exaggerated

Behavioural Pharmacology ◽

10.1097/fbp.0b013e3283566a8c ◽

2012 ◽

Vol 23 (5 and 6) ◽

pp. 537-550 ◽

Cited By ~ 19

Author(s):

Peter J. McLaughlin

Keyword(s):

Cb1 Antagonists

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Exploring SAR features in diverse library of 4-cyanomethyl-pyrazole-3-carboxamides suitable for further elaborations as CB1 antagonists

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2009.11.047 ◽

2010 ◽

Vol 20 (1) ◽

pp. 26-30 ◽

Cited By ~ 21

Author(s):

Martin Cooper ◽

Jean-Marie Receveur ◽

Emelie Bjurling ◽

Pia K. Nørregaard ◽

Peter Aadal Nielsen ◽

...

Keyword(s):

Cb1 Antagonists

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Pharmacokinetic optimisation of novel indole-2-carboxamide cannabinoid CB1 antagonists

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2011.02.019 ◽

2011 ◽

Vol 21 (7) ◽

pp. 2034-2039 ◽

Cited By ~ 2

Author(s):

Phillip M. Cowley ◽

James Baker ◽

Kirsteen I. Buchanan ◽

Ian Carlyle ◽

John K. Clark ◽

...

Keyword(s):

Cb1 Antagonists

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Resistance to epinephrine and hypersensitivity (hyperresponsiveness) to CB1 antagonists in a patient with pseudohypoparathyroidism type Ic

Acta Endocrinologica ◽

10.1530/eje-09-0951 ◽

2010 ◽

Vol 162 (4) ◽

pp. 819-824 ◽

Cited By ~ 8

Author(s):

Abdallah Al-Salameh ◽

F Despert ◽

Marie-Laure Kottler ◽

Agnès Linglart ◽

Jean-Claude Carel ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Normal Activity ◽

Response To Treatment ◽

Melanocortin 4 Receptor ◽

Cb1 Antagonist ◽

Disorder Treatment ◽

Cb1 Antagonists ◽

Gnas Mutation

Pseudohypoparathyroidism (PHP) covers a heterogeneous group of disorders, which have in common resistance to parathyroid hormone (PTH). However, they differ in many aspects such as site of the defect in signal transduction, clinical picture (with or without Albright's hereditary osteodystrophy (AHO)), extension of hormone resistance, and the tissue activity of protein Gs. PHP type Ic, a rare subtype, is characterized by resistance to several hormones, the presence of AHO, and normal activity of protein Gs. We present the case of a patient with PHP type Ic. Although resistance to TSH was suggested at the age of 12 months, diagnosis was made when she presented with hypocalcemia and resistance to PTH. Resistance to GH was also detected, and partial resistance to gonadotropins became clear after puberty. We demonstrated a defective lipolytic response to epinephrine, suggesting a role of this resistance in the pathogenesis of her morbid obesity. In view of the difficulties in the management of overweight in this disorder, treatment with a cannabinoid receptor type 1 (CB1) antagonist was started, and it proved to be highly effective, lowering the patient's body mass index from 40.5 to 33.5, which was quite impressive. We propose that an underactive melanocortin-4 receptor, which is found in certain patients with PHP, leads to upregulation of the CB1 receptor and consequently to a good response to treatment with CB1 antagonists. Another interesting finding was the GNAS mutation that was identified in this patient. A nonsense mutation resulted in a truncated Gsa that was able to stimulate adenylyl cyclase efficiently, but could not bind to receptors in a normal way.

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