Novel 1′,1′‐Chain Substituted Δ<sup>8</sup>‐Tetrahydrocannabinols.

Papahatjis, Demetris P.; Nikas, Spyros P.; Andreou, Thanos; Makriyannis, Alexandros

doi:10.1002/chin.200312163

Cited by 11 publications

(33 citation statements)

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“…CBD competes poorly with cannabinoid receptor ligand binding to cannabinoid receptors (Thomas et al, 1998), leading to an initial (and persistent) conclusion that any action of CBD necessarily occurs through noncannabinoid receptors. It may seem surprising that CBD and THC are structurally similar (and with the same molecular weight) yet exhibit different orthosteric binding to CB1 receptors, but this may be accounted for by steric differences between these molecules as explored in structure-activity studies (e.g., Papahatjis et al, 2002). However, it subsequently became clear that CBD does interfere with cannabinoid function at a potency greater than that expected based on the earlier orthosteric binding data (Thomas et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons

Straiker¹,

Dvořáková²,

Zimmowitch³

et al. 2018

Mol Pharmacol

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Δ-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two main cannabinoid constituents of marijuana and hashish. The pharmacology of Δ-THC has been extensively studied, whereas our understanding of the pharmacology of CBD has remained limited, despite excitement in CBD's potential role in treating certain pediatric epilepsies and its reputation for attenuating some Δ-THC-induced effects. It was established early on that CBD binds poorly to the orthosteric site of CB or CB cannabinoid receptors, and its actions were commonly attributed to other noncannabinoid receptor mechanisms. However, recent evidence suggests that CBD does indeed act at cannabinoid CB receptors as a negative allosteric modulator (NAM) of CB signaling. By altering the orthosteric signaling of a G protein-coupled receptor, allosteric modulators greatly increase the richness of G protein-coupled receptor pharmacology. We have recently surveyed candidate CB NAMs in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and have now tested CBD in this model. We find that although CBD has no direct effect on excitatory transmission, it does inhibit two forms of endogenous cannabinoid-mediated retrograde synaptic plasticity: depolarization-induced suppression of excitation and metabotropic suppression of excitation, while not affecting signaling via GABA-B receptors. These results are consistent with the recently described NAM activity of CBD and suggest interesting possible mechanisms for CBD's therapeutic actions.

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Section: Discussionmentioning

confidence: 99%

Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons

Straiker¹,

Dvořáková²,

Zimmowitch³

et al. 2018

Mol Pharmacol

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“…Transforming the 1',1'-geminal dimethyl substitution into a compact cyclopropyl ring further enhances activity at both receptors. 94 Expanding the ring size to 4, 5, and 6 carbons modulates the activity as a function of the lowest energy conformation of the alkyl chain, as well as the presence of hydrophobic bulk, potentially creating steric clashes with the putative binding site in the receptor. Quantitative structure–activity relationship studies confirm that the cyclopropyl and cyclopentyl rings force the chain into similar favorable orientations, with the cyclobutyl- and cyclohexyl-substituted chains adopting less favorable conformations for optimal receptor binding.…”

Section: Synthetic Classical Cannabinoidsmentioning

confidence: 99%

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Bow

Rimoldi

2016

Perspect Medicin Chem

108

111

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The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles.

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“…11,12 Subsequent work has established that the side chain plays a pivotal role in modulating cannab-inergic potency. [13][14][15][16][17][18][19] Earlier work from our laboratory has explored the pharmacophoric requirements of the side chain within the classical tetrahydrocannabinol (THC) template. This included conformational restriction through the inclusion of multiple bonds within the chain, the addition of C1′ cyclic substituents, 17,18 and the incorporation of the first one or two side chain carbons into a six-membered ring fused with the phenolic A ring.…”

Section: Introductionmentioning

confidence: 99%

Adamantyl Cannabinoids: A Novel Class of Cannabinergic Ligands

Meng

Thakur

et al. 2005

J. Med. Chem.

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Structure-activity relationship studies have established that the aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have now synthesized a series of analogues in which a variety of adamantyl substituents were introduced at the C3 position of Delta(8)-THC. Our lead compound, (-)-3-(1-adamantyl)-Delta(8)-tetrahydrocannabinol (1a, AM411), was found to have robust affinity and selectivity for the CB1 receptor as well as high in vivo potency. The X-ray crystal structure of 1a was determined. Exploration of the side chain conformational space using molecular modeling approaches has allowed us to develop cannabinoid side chain pharmacophore models for the CB1 and CB2 receptors. Our results suggest that although a bulky group at the C3 position of classical cannabinoids could be tolerated by both CB1 and CB2 binding sites, the relative orientation of that group with respect to the tricyclic component can lead to receptor subtype selectivity.

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Novel 1′,1′‐Chain Substituted Δ⁸‐Tetrahydrocannabinols.

Cited by 11 publications

References 1 publication

Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons

Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Adamantyl Cannabinoids: A Novel Class of Cannabinergic Ligands

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Novel 1′,1′‐Chain Substituted Δ8‐Tetrahydrocannabinols.

Cited by 11 publications

References 1 publication

Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons

Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Adamantyl Cannabinoids: A Novel Class of Cannabinergic Ligands

Contact Info

Product

Resources

About

Novel 1′,1′‐Chain Substituted Δ⁸‐Tetrahydrocannabinols.