scholarly journals Why does Δ9-Tetrahydrocannabinol act as a partial agonist of cannabinoid receptors?

2021 ◽  
Author(s):  
Soumajit Dutta ◽  
Balaji Selvam ◽  
Aditi Das ◽  
Diwakar Shukla
Keyword(s):  
Side Effects ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Transmembrane Helix ◽  
Toggle Switch ◽  
Agonist Binding ◽  
Partial Agonism ◽  
Partial Agonists ◽  
Agonist And Antagonist

AbstractCannabinoid receptor 1 (CB1) is a therapeutically relevant drug target for controlling pain, obesity, and other central nervous system disorders. However, full agonists and antagonists of CB1 have been reported to cause serious side effects in patients. Therefore, partial agonists have emerged as a viable alternative to full agonists and antagonists as they avoid overstimulation and side effects. One of the key bottlenecks in the design of partial agonists is the lack of understanding of the molecular mechanism of partial agonism. In this study, we examine two mechanistic hypotheses for the origin of partial agonism in cannabinoid receptors and explain the mechanistic basis of partial agonism exhibited by Δ9-Tetrahydrocannabinol (THC). In particular, we inspect whether partial agonism emerges from the ability of THC to bind in both agonist and antagonist binding pose or from its ability to only partially activate the receptor. Extensive molecular dynamics simulations and the Markov state model capture the THC binding in both antagonist, and agonist binding poses in CB1 receptor. Furthermore, we observe that binding of THC in the agonist binding pose leads to rotation of toggle switch residues and causes partial outward movement of intracellular transmembrane helix 6 (TM6). Our simulations also suggest that the alkyl side chain of THC plays a crucial role in determining partial agonism by stabilizing the ligand in the agonist and antagonist-like poses within the pocket. This study provides us fundamental insights into the mechanistic origin of the partial agonism of THC.

scholarly journals Probing the β2 Adrenoceptor Binding Site with Catechol Reveals Differences in Binding and Activation by Agonists and Partial Agonists

2005 ◽  
Vol 280 (23) ◽  
pp. 22165-22171 ◽  
Author(s):  
Gayathri Swaminath ◽  
Xavier Deupi ◽  
Tae Weon Lee ◽  
Wen Zhu ◽  
Foon Sun Thian ◽  
...  
Keyword(s):  
Binding Site ◽  
Aromatic Ring ◽  
Partial Agonist ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Molecular Probe ◽  
Toggle Switch ◽  
Partial Agonists ◽  
Gpcr Activation ◽  
Multistep Process

The β2 adrenergic receptor (β2AR) is a prototypical family A G protein-coupled receptor (GPCR) and an excellent model system for studying the mechanism of GPCR activation. The β2AR agonist binding site is well characterized, and there is a wealth of structurally related ligands with functionally diverse properties. In the present study, we use catechol (1,2-benzenediol, a structural component of catecholamine agonists) as a molecular probe to identify mechanistic differences between β2AR activation by catecholamine agonists, such as isoproterenol, and by the structurally related non-catechol partial agonist salbutamol. Using biophysical and pharmacologic approaches, we show that the aromatic ring of salbutamol binds to a different site on the β2AR than the aromatic ring of catecholamines. This difference is important in receptor activation as it has been hypothesized that the aromatic ring of catecholamines plays a role in triggering receptor activation through interactions with a conserved cluster of aromatic residues in the sixth transmembrane segment by a rotamer toggle switch mechanism. Our experiments indicate that the aromatic ring of salbutamol does not activate this mechanism either directly or indirectly. Moreover, the non-catechol ring of partial agonists does not interact optimally with serine residues in the fifth transmembrane helix that have been shown to play an important role in activation by catecholamines. These results demonstrate unexpected differences in binding and activation by structurally similar agonists and partial agonists. Moreover, they provide evidence that activation of a GPCR is a multistep process that can be dissected into its component parts using agonist fragments.

The importance of interactions with helix 5 in determining the efficacy of β-adrenoceptor ligands

2013 ◽  
Vol 41 (1) ◽  
pp. 159-165 ◽  
Author(s):  
Tony Warne ◽  
Christopher G. Tate
Keyword(s):  
Transmembrane Helix ◽  
Binding Pocket ◽  
Pharmacological Properties ◽  
Agonist Binding ◽  
Inverse Agonists ◽  
Inactive State ◽  
Partial Agonists ◽  
Activated State

Structures of the inactive state of the thermostabilized β1-adrenoceptor have been determined bound to eight different ligands, including full agonists, partial agonists, inverse agonists and biased agonists. Comparison of the structures shows distinct differences within the binding pocket that correlate with the pharmacological properties of the ligands. These data suggest that full agonists stabilize a structure with a contracted binding pocket and a rotamer change of serine (5.46) compared with when antagonists are bound. Inverse agonists may prevent both of these occurrences, whereas partial agonists stabilize a contraction of the binding pocket but not the rotamer change of serine (5.46). It is likely that subtle changes in the interactions between transmembrane helix 5 (H5) and H3/H4 on agonist binding promote the formation of the activated state.

scholarly journals Spinal Cannabinoid Receptor Type 2 Activation Reduces Hypersensitivity and Spinal Cord Glial Activation after Paw Incision

2007 ◽  
Vol 106 (4) ◽  
pp. 787-794 ◽  
Author(s):  
Alfonso Romero-Sandoval ◽  
James C. Eisenach
Keyword(s):  
Spinal Cord ◽  
Side Effects ◽  
Receptor Antagonist ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Intrathecal Injection ◽  
Intrathecal Administration ◽  
Glial Activation ◽  
Receptor Agonists ◽  
Cannabinoid 1 Receptor

Background Cannabinoids bind to cannabinoid receptors type 1 and 2 and produce analgesia in several pain models, but central side effects from cannabinoid 1 receptors limit their clinical use. Cannabinoid 2 receptors reduce inflammatory responses in the periphery by acting on immune cells, and they are present on glia in the central nervous system. This study tested whether spinal cannabinoid activation would induce analgesia, glial inhibition, and central side effects in a postoperative model or incisional pain. Methods Rats underwent paw incision surgery, with intrathecal injections of cannabinoid agonists and antagonists and assessment of withdrawal thresholds and behavioral side effects. Spinal glial activation was determined by immunohistochemistry. Results Intrathecal administration CP55940 reduced postoperative hypersensitivity (91 +/- 9% maximum possible effect; P < 0.05), and this was prevented by intrathecal administration of both cannabinoid 1 receptor (AM281) and cannabinoid 2 receptor (AM630) antagonists. CP55940 also caused several behavioral side effects, and these were prevented by the cannabinoid 1 receptor but not by the cannabinoid 2 receptor antagonist. Intrathecal injection of the cannabinoid 2 receptor agonist JWH015 reversed postoperative hypersensitivity (89 +/- 5% maximum possible effect; P < 0.05), and this was reversed by the cannabinoid 2 but not by the cannabinoid 1 receptor antagonist. JWH015, which did not induce behavioral side effects, reduced paw incision induced microglial and astrocytic activation in spinal cord (P < 0.05). Conclusions These data indicate that intrathecal administration of cannabinoid receptor agonists may provide postoperative analgesia while reducing spinal glial activation, and that selective cannabinoid 2 receptor agonists may do so without central side effects.

scholarly journals Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ayat Zagzoog ◽  
Asher L. Brandt ◽  
Tallan Black ◽  
Eunhyun D. Kim ◽  
Riley Burkart ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Synthetic Cannabinoid ◽  
Receptor Subtype ◽  
Service Agency ◽  
Subtype Selectivity ◽  
Insight Into

AbstractThe first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs—JWH-018 2′-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.

scholarly journals Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol

2020 ◽  
Vol 71 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Katarina Černe
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Liver Toxicity ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Safety Issue ◽  
Receptor Ligands ◽  
Toxicological Effects ◽  
Neuropsychological Effects ◽  
The Central Nervous System

AbstractCannabis sativa L. contains more than 100 phytocannabinoids that can interact with cannabinoid receptors CB1 and CB2. None of the cannabinoid receptor ligands is entirely CB1- or CB2-specific. The effects of cannabinoids therefore differ not just because of different potency at cannabinoid receptors but also because they can interact with other non-CB1 and non-CB2 targets, such as TRPV1, GPR55, and GPR119. The most studied phytocannabinoid is Δ9-tetrahydrocannabinol (THC). THC is a partial agonist at both cannabinoid receptors, but its psychotomimetic effect is produced primarily via activation of the CB1 receptor, which is strongly expressed in the central nervous system, with the noteworthy exception of the brain stem. Although acute cognitive and other effects of THC are well known, the risk of irreversible neuropsychological effects of THC needs further research to elucidate the association. Unlike THC, phytocannabinoid cannabidiol (CBD) does not appear to have psychotomimetic effects but may interact with some of the effects of THC if taken concomitantly. CBD administered orally has recently undergone well-controlled clinical trials to assess its safety in the treatment of paediatric epilepsy syndromes. Their findings point to increased transaminase levels as a safety issue that calls for postmarketing surveillance for liver toxicity. The aim of this review is to summarise what is known about acute and chronic toxicological effects of both compounds and address the gaps in knowledge about the safety of exogenous cannabinoids that are still open.

scholarly journals Photolabelling the urotensin II receptor reveals distinct agonist- and partial-agonist-binding sites

2007 ◽  
Vol 402 (1) ◽  
pp. 51-61 ◽  
Author(s):  
Brian J. Holleran ◽  
Marie-Eve Beaulieu ◽  
Christophe D. Proulx ◽  
Pierre Lavigne ◽  
Emanuel Escher ◽  
...  
Keyword(s):  
Binding Site ◽  
Conformational Changes ◽  
Binding Sites ◽  
Transmembrane Domain ◽  
Partial Agonist ◽  
Binding Pocket ◽  
Activation Mechanism ◽  
Urotensin Ii ◽  
Agonist Binding ◽  
Partial Agonists

The mechanism by which GPCRs (G-protein-coupled receptors) undergo activation is believed to involve conformational changes following agonist binding. We have used photoaffinity labelling to identify domains within GPCRs that make contact with various photoreactive ligands in order to better understand the activation mechanism. Here, a series of four agonist {[Bpa1]U-II (Bpa is p-benzoyl-L-phenylalanine), [Bpa2]U-II, [Bpa3]U-II and [Bpa4]U-II} and three partial agonist {[Bpa1Pen5D-Trp7Orn8]U-II (Pen is penicillamine), [Bpa2Pen5D-Trp7Orn8]U-II and [Pen5Bpa6D-Trp7Orn8]U-II} photoreactive urotensin II (U-II) analogues were used to identify ligand-binding sites on the UT receptor (U-II receptor). All peptides bound the UT receptor expressed in COS-7 cells with high affinity (Kd of 0.3–17.7 nM). Proteolytic mapping and mutational analysis led to the identification of Met288 of the third extracellular loop of the UT receptor as a binding site for all four agonist peptides. Both partial agonists containing the photoreactive group in positions 1 and 2 also cross-linked to Met288. We found that photolabelling with the partial agonist containing the photoreactive group in position 6 led to the detection of transmembrane domain 5 as a binding site for that ligand. Interestingly, this differs from Met184/Met185 of the fourth transmembrane domain that had been identified previously as a contact site for the full agonist [Bpa6]U-II. These results enable us to better map the binding pocket of the UT receptor. Moreover, the data also suggest that, although structurally related agonists or partial agonists may dock in the same general binding pocket, conformational changes induced by various states of activation may result in slight differences in spatial proximity within the cyclic portion of U-II analogues.

Fluorescence Characteristics of Hydrophobic Partial Agonist Probes of the Cholecystokinin Receptor

2006 ◽  
Vol 26 (2) ◽  
pp. 89-100 ◽  
Author(s):  
Kaleeckal G. Harikumar ◽  
Delia I. Pinon ◽  
Laurence J. Miller
Keyword(s):  
Partial Agonist ◽  
Receptor Activation ◽  
Spectroscopic Studies ◽  
Dynamic Changes ◽  
Full Agonist ◽  
Cholecystokinin Receptor ◽  
Partial Agonists ◽  
Receptor Structure ◽  
Fluorescence Characteristics ◽  
Agonist And Antagonist

Fluorescence spectroscopic studies are powerful tools for the evaluation of receptor structure and the dynamic changes associated with receptor activation. Here, we have developed two chemically distinct fluorescent probes of the cholecystokinin (CCK) receptor by attaching acrylodan or a nitrobenzoxadiazole moiety to the amino terminus of a partial agonist CCK analogue. These two probes were able to bind to the CCK receptor specifically and with high affinity, and were able to elicit only submaximal intracellular calcium responses typical of partial agonists. The fluorescence characteristics of these probes were compared with those previously reported for structurally-related full agonist and antagonist probes. Like the previous probes, the partial agonist probes exhibited longer fluorescence lifetimes and increased anisotropy when bound to the receptor than when free in solution. The receptor-bound probes were not easily quenched by potassium iodide, suggesting that the fluorophores were protected from the extracellular aqueous milieu. The fluorescence characteristics of the partial agonist probes were quite similar to those of the analogous full agonist probes and quite distinct from the analogous antagonist probes. These data suggest that the partially activated conformational state of this receptor is more closely related to its fully active state than to its inactive state.

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

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1656
Author(s):  
Gabriele Murineddu ◽  
Battistina Asproni ◽  
Paola Corona ◽  
Sandra Piras ◽  
Paolo Lazzari ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Gastrointestinal Transit ◽  
In Vitro Tests ◽  
Significant Activity ◽  
Cannabinoid Receptor 1 ◽  
Antagonist Activity ◽  
Cb1 Antagonist

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 (KiCB1 = 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.

scholarly journals Differential Cannabinoid Receptor Expression during Reactive Gliosis: a Possible Implication for a Nonpsychotropic Neuroprotection

2009 ◽  
Vol 9 ◽  
pp. 229-235 ◽  
Author(s):  
Daniele De Filippis ◽  
Antonio Steardo ◽  
Alessandra D'Amico ◽  
Caterina Scuderi ◽  
Mariateresa Cipriano ◽  
...  
Keyword(s):  
Side Effects ◽  
Neurodegenerative Disorders ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Receptor Expression ◽  
Pharmacological Activities ◽  
Great Ability ◽  
Psychotropic Effect

Activated microglia and astrocytes produce a large number of inflammatory and neurotoxic substances in various brain pathologies, above all during neurodegenerative disorders. In the search for new neuroprotective compounds, interest has turned to marijuana derivatives, since in severalin vitro,in vivo, and clinical studies, they have shown a great ability to control neuroinflammation.Despite the emerging evidence regarding pharmacological activities of cannabinoids, their effective introduction into clinical therapy still remains controversial and strongly limited by their unavoidable psychotropicity. Since the psychotropic effect of cannabinoids is generally linked to the activation of the CB1 receptor on neurons, the aim of our review is to clarify the function of the two cannabinoid receptors on glial cells and the differential role played by them, highlighting the emerging evidence of a CB2-mediated control of neuroinflammation that could liberate cannabinoids from the slavery of their central side effects.

scholarly journals In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ayat Zagzoog ◽  
Kawthar A. Mohamed ◽  
Hye Ji J. Kim ◽  
Eunhyun D. Kim ◽  
Connor S. Frank ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Chinese Hamster ◽  
Cannabidiolic Acid

AbstractThe Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆9-THC is known to bring about the ‘high’ associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆9-THC, ∆9-tetrahydrocannabinolic acid (∆9-THCa), ∆9-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.

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