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Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 50324

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Special Issue Editor

Prof. Dr. Spyros P. Nikas

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Guest Editor

Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
Interests: drug discovery; bioactive molecules; specialized probes for GPCRs; cannabinoid receptor modulators; endocannabinoid enzyme inhibitors; prostaglandins; melatonin receptor probes; synthetic methods; hypervalent iodine

Special Issue Information

Dear Colleagues,

The endocannabinoid (eCB) biochemical system encompasses receptors; their endogenous ligands; and the enzymes responsible for their synthesis, transport, hydrolysis, and oxidative metabolisms. Research involving the eCB system is generating strong interest because of the therapeutic potential of drugs that can modulate the function of endocannabinoid proteins. Thus, targeting the endocannabinoid receptors and enzymes with small molecules is a promising therapeutic approach to treat an array of indications including pain, inflammation, CNS and cardiometabolic disorders, glaucoma, and cancer. Currently, there are four marketed cannabinoid drugs, and a few more are undergoing clinical trials. This Issue will contain articles on the medicinal chemistry and pharmacology of cannabinergic ligands. Such ligands will include, orthosteric and allosteric modulators of the CB1/CB2 cannabinoid receptors, inhibitors of the endocannabinoid-regulating enzymes, as well as bioactive metabolites of the endogenous cannabinoids. Specialized cannabinergic ligands such as isotopically labelled and imaging agents, as well as ligands for closely related GPCR targets such as GPR18, GPR55, GPR119, and TRPV1, will also be covered.

Prof. Dr. Spyros P. Nikas
Guest Editor

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Keywords

Cannabinoid receptor modulators
Endocannabinoid enzyme inhibitors
Endogenous/exogenous cannabinoids
Prostaglandins
Pain
Inflammation
CNS disorders
Cardiometabolic disorders
Glaucoma
Cancer

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Published Papers (10 papers)

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Research

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13 pages, 1762 KiB

Open AccessArticle

Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells

by Francesca Gado, Rebecca Ferrisi, Sarah Di Somma, Fabiana Napolitano, Kawthar A. Mohamed, Lesley A. Stevenson, Simona Rapposelli, Giuseppe Saccomanni, Giuseppe Portella, Roger G. Pertwee, Robert B. Laprairie, Anna Maria Malfitano and Clementina Manera

Molecules 2022, 27(9), 3019; https://doi.org/10.3390/molecules27093019 - 7 May 2022

Cited by 4 | Viewed by 2766

Abstract

1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent β-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC₅₀ of FG158a = 11.8 μM and FG160a = 13.2 μM in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a, was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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14 pages, 5000 KiB

Open AccessArticle

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome

by Basma G. Eid, Thikryat Neamatallah, Abeer Hanafy, Hany M. El-Bassossy, Lenah Binmahfouz, Hibah M. Aldawsari, Atif Hasan, Gamal Abd El-Aziz, Kiran Vemuri and Alexandros Makriyannis

Molecules 2021, 26(4), 866; https://doi.org/10.3390/molecules26040866 - 6 Feb 2021

Cited by 11 | Viewed by 2925 | Correction

Abstract

The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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12 pages, 1188 KiB

Open AccessArticle

Synthesis of Functionalized Cannabilactones

by Yingpeng Liu, Thanh C. Ho, Mohammed Baradwan, Maria Pascual Lopez-Alberca, Christos Iliopoulos-Tsoutsouvas, Spyros P. Nikas and Alexandros Makriyannis

Molecules 2020, 25(3), 684; https://doi.org/10.3390/molecules25030684 - 6 Feb 2020

Cited by 4 | Viewed by 4783

Abstract

A new approach to synthesize cannabilactones using Suzuki cross-coupling reaction followed by one-step demethylation-cyclization is presented. The two key cannabilactone prototypes AM1710 and AM1714 were obtained selectively in high overall yields and in a lesser number of synthetic steps when compared to our earlier synthesis. The new approach expedited the synthesis of cannabilactone analogs with structural modifications at the four potential pharmacophoric regions. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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11 pages, 2997 KiB

Open AccessArticle

Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation

by Dinesh Thapa, Elizabeth A. Cairns, Anna-Maria Szczesniak, Pushkar M. Kulkarni, Alex J. Straiker, Ganesh A. Thakur and Melanie E. M. Kelly

Molecules 2020, 25(2), 417; https://doi.org/10.3390/molecules25020417 - 20 Jan 2020

Cited by 32 | Viewed by 7334

Abstract

Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury. We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia. Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2^−/−) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ⁸-tetrahydrocannabinol (Δ⁸-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation. Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ⁸-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2^−/− mice. Two percent GAT228, or the combination of 0.2% Δ⁸-THC with 0.5% GAT229 also significantly reduced corneal inflammation. CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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10 pages, 841 KiB

Open AccessArticle

Identification of Cannabis sativa L. (hemp) Retailers by Means of Multivariate Analysis of Cannabinoids

by Sara Palmieri, Marcello Mascini, Antonella Ricci, Federico Fanti, Chiara Ottaviani, Claudio Lo Sterzo and Manuel Sergi

Molecules 2019, 24(19), 3602; https://doi.org/10.3390/molecules24193602 - 7 Oct 2019

Cited by 15 | Viewed by 5304

Abstract

In this work, the concentration of nine cannabinoids, six neutral cannabinoids (THC, CBD, CBC, CBG, CBN and CBDV) and three acidic cannabinoids (THCA CBGA and CBDA), was used to identify the Italian retailers of Cannabis sativa L. (hemp), reinforcing the idea that the practice of categorizing hemp samples only using THC and CBD is inadequate. A high-performance liquid chromatography/high-resolution mass spectrometry (HPLC-MS/MS) method was developed for screening and simultaneously analyzing the nine cannabinoids in 161 hemp samples sold by four retailers located in different Italian cities. The hemp samples dataset was analyzed by univariate and multivariate analysis with the aim to identify the hemp retailers without any other information on the hemp samples like Cannabis strains, seeds, soil and cultivation characteristics, geographical origin, product storage, etc. The univariate analysis highlighted that the hemp samples could not be differentiated by using any of the nine cannabinoids analyzed. To evaluate the real efficiency of the discrimination among the four hemp retailers a partial least squares discriminant analysis (PLS-DA) was applied. The PLS-DA results showed a very good discrimination between the four hemp retailers with an explained variance of 100% and low classification errors in both calibration (5%) and cross validation (6%). A total of 92% of the hemp samples were correctly classified by the cannabinoid variables in both fitting and cross validation. This work contributed to show that an analytical method coupled with multivariate analysis can be used as a powerful tool for forensic purposes. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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21 pages, 4322 KiB

Open AccessArticle

Chain Substituted Cannabilactones with Selectivity for the CB2 Cannabinoid Receptor

by Shakiru O. Alapafuja, Spyros P. Nikas, Thanh C. Ho, Fei Tong, Othman Benchama and Alexandros Makriyannis

Molecules 2019, 24(19), 3559; https://doi.org/10.3390/molecules24193559 - 1 Oct 2019

Cited by 6 | Viewed by 4467

Abstract

In earlier work, we reported a novel class of CB2 selective ligands namely cannabilactones. These compounds carry a dimethylheptyl substituent at C3, which is typical for synthetic cannabinoids. In the current study with the focus on the pharmacophoric side chain at C3 we explored the effect of replacing the C1′-gem-dimethyl group with the bulkier cyclopentyl ring, and, we also probed the chain’s length and terminal carbon substitution with bromo or cyano groups. One of the analogs synthesized namely 6-[1-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl) cyclopentyl] hexanenitrile (AM4346) has very high affinity (K_i = 4.9 nM) for the mouse CB2 receptor (mCB2) and 131-fold selectivity for that target over the rat CB1 (rCB1). The species difference in the affinities of AM4346 between the mouse (m) and the human (h) CB2 receptors is reduced when compared to our first-generation cannabilactones. In the cyclase assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC₅₀ = 3.7 ± 1.5 nM, E_(max) = 89%). We have also extended our structure-activity relationship (SAR) studies to include biphenyl synthetic intermediates that mimic the structure of the phytocannabinoid cannabinodiol. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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20 pages, 2471 KiB

Open AccessArticle

Selective Cannabinoid 2 Receptor Agonists as Potential Therapeutic Drugs for the Treatment of Endotoxin-Induced Uveitis

by Richard Frederick Porter, Anna-Maria Szczesniak, James Thomas Toguri, Simon Gebremeskel, Brent Johnston, Christian Lehmann, Jürgen Fingerle, Benno Rothenhäusler, Camille Perret, Mark Rogers-Evans, Atsushi Kimbara, Matthias Nettekoven, Wolfgang Guba, Uwe Grether, Christoph Ullmer and Melanie E. M. Kelly

Molecules 2019, 24(18), 3338; https://doi.org/10.3390/molecules24183338 - 13 Sep 2019

Cited by 21 | Viewed by 5916

Abstract

(1) Background: The cannabinoid 2 receptor (CB₂R) is a promising anti-inflammatory drug target and development of selective CB₂R ligands may be useful for treating sight-threatening ocular inflammation. (2) Methods: This study examined the pharmacology of three novel chemically-diverse selective CB₂R ligands: CB₂R agonists, RO6871304, and RO6871085, as well as a CB₂R inverse agonist, RO6851228. In silico molecular modelling and in vitro cell-based receptor assays were used to verify CB₂R interactions, binding, cell signaling (ß-arrestin and cAMP) and early absorption, distribution, metabolism, excretion, and toxicology (ADMET) profiling of these receptor ligands. All ligands were evaluated for their efficacy to modulate leukocyte-neutrophil activity, in comparison to the reported CB₂R ligand, HU910, using an in vivo mouse model of endotoxin-induced uveitis (EIU) in wild-type (WT) and CB₂R^-/- mice. The actions of RO6871304 on neutrophil migration and adhesion were examined in vitro using isolated neutrophils from WT and CB₂R^-/- mice, and in vivo in WT mice with EIU using adoptive transfer of WT and CB₂R^-/- neutrophils, respectively. (3) Results: Molecular docking studies indicated that RO6871304 and RO6871085 bind to the orthosteric site of CB₂R. Binding studies and cell signaling assays for RO6871304 and RO6871085 confirmed high-affinity binding to CB₂R and selectivity for CB₂R > CB₁R, with both ligands acting as full agonists in cAMP and ß-arrestin assays (EC₅₀s in low nM range). When tested in EIU, topical application of RO6871304 and RO6871085 decreased leukocyte-endothelial adhesion and this effect was antagonized by the inverse agonist, RO6851228. The CB₂R agonist, RO6871304, decreased in vitro neutrophil migration of WT neutrophils but not neutrophils from CB₂R^-/-, and attenuated adhesion of adoptively-transferred leukocytes in EIU. (4) Conclusions: These unique ligands are potent and selective for CB₂R and have good immunomodulating actions in the eye. RO6871304 and RO6871085, as well as HU910, decreased leukocyte adhesion in EIU through inhibition of resident ocular immune cells. The data generated with these three structurally-diverse and highly-selective CB₂R agonists support selective targeting of CB₂R for treating ocular inflammatory diseases. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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22 pages, 5895 KiB

Open AccessArticle

Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands

by Gabriele Murineddu, Battistina Asproni, Paola Corona, Sandra Piras, Paolo Lazzari, Stefania Ruiu, Laura Legnani, Lucio Toma and Gérard A. Pinna

Molecules 2019, 24(9), 1656; https://doi.org/10.3390/molecules24091656 - 27 Apr 2019

Cited by 5 | Viewed by 3641

Abstract

In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta[1,2-c]pyrazole-3-carboxamide 1a and its deaza N-cyclohexyl analogue 1b has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of 1a,b, derivatives 1c–j, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays. Among the derivatives, 1d and 1e resulted in the most potent CB₁ receptor ligands (K_iCB₁ = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB₁ antagonist activity for the majority of the new compounds, excluding compound 1e, which showed a CB₁ partial agonist behaviour. CB₁ antagonist activity of 1b was further confirmed by a mouse gastrointestinal transit assay. Significant activity of the new CB₁ antagonists towards food intake was showed by preliminary acute assays, evidencing the potentiality of these new derivatives in the treatment of obesity. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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Review

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14 pages, 3164 KiB

Open AccessReview

Post-Harvest Operations to Generate High-Quality Medicinal Cannabis Products: A Systemic Review

by Hebah Muhsien Sabiah AL Ubeed, Ronald B. H. Wills and Jayani Chandrapala

Molecules 2022, 27(5), 1719; https://doi.org/10.3390/molecules27051719 - 6 Mar 2022

Cited by 19 | Viewed by 10577

Abstract

The traditional Cannabis plant as a medicinal crop has been explored for many thousands of years. The Cannabis industry is rapidly growing; therefore, optimising drying methods and producing high-quality medical products have been a hot topic in recent years. We systemically analysed the current literature and drew a critical summary of the drying methods implemented thus far to preserve the quality of bioactive compounds from medicinal Cannabis. Different drying techniques have been one of the focal points during the post-harvesting operations, as drying preserves these Cannabis products with increased shelf life. We followed or even highlighted the most popular methods used. Drying methods have advanced from traditional hot air and oven drying methods to microwave-assisted hot air drying or freeze-drying. In this review, traditional and modern drying technologies are reviewed. Each technology will have different pros and cons of its own. Moreover, this review outlines the quality of the Cannabis plant component harvested plays a major role in drying efficiency and preserving the chemical constituents. The emergence of medical Cannabis, and cannabinoid research requires optimal post-harvesting processes for different Cannabis strains. We proposed the most suitable method for drying medicinal Cannabis to produce consistent, reliable and potent medicinal Cannabis. In addition, drying temperature, rate of drying, mode and storage conditions after drying influenced the Cannabis component retention and quality. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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