Article

Tetrahydrocannabinol Homologs. XVII.1

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Roger Adams synthesized the first synthetic cannabinoids in the 1940's, through side chain modification of tetrahydrocannabinol (THC) (Adams et al., 1948). The SCs HU-210 and CP-47,497 were then synthesized in the 1980's, followed by WIN55, 212-1 in the early 1990's. ...
Article
Synthetic cannabinoids (SC), are a novel class of designer drugs which emerged as a drug of abuse in the late 2000's. We report a case series of 6 patients who may have smoked a synthetic cannabinoid product in a remote wilderness setting. They presented with varying degrees of altered mental status, agitation, and seizures. Two were confirmed to have AB-PINACA, ADB-PINACA and their respective pentanoic acid metabolites in biological specimens via liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS). Both compounds had DEA Schedule I classification at the time of case presentation, and 22 SCs are currently temporary or permanent DEA Schedule I. More than 150 SCs are known to date, and new compounds are appearing at a rapid rate on darknet and surface web e-commerce websites, marketed as "research chemicals" or "legal highs." The scale and rapidity of SC evolution make legal control and analytical detection difficult. Nontargeted testing with liquid chromatography high resolution mass spectrometry (LC-HRMS), examining both parent compounds and metabolites, is the ideal method for novel SC identification and confirmation. Due to full agonism at the cannabinoid receptors CB1 and CB2, clinical effects are more severe than marijuana, which is a partial cannabinoid receptor agonist. They include agitated delirium, lethargy and coma, seizures, tachycardia, hypertension, and hallucinations, among other findings. Treatment is primarily symptomatic and aimed at airway protection and control of agitation and seizures. SCs do not appear to be abating anytime soon and require the cooperation of law enforcement, analytical scientists, and clinicians to adequately control.
Article
Full-text available
Endocannabinoid signalling is considered one of the most important modulatory systems in a whole organism. Research has yielded great insight on the mechanisms that link endocannabinoids and metabolic functions. Here, we provide a brief overview of the metabolic roles of endocannabinoids in tissue, cellular and subcellular-dependent mechanisms. In general, we point out how the central and peripheral control of body energy metabolism likely represents the main function of type-1 cannabinoid receptors. More specifically, we focus on recent advances underlying mechanisms of endocannabinoid control of cell metabolism through the modulation of the functions of specific organelles. While highlighting a historical summary and summarizing past discoveries, this short review aims at proposing future open questions for a field that does not stop surprising researchers with unexpected and exciting discoveries. Busquets-García et al. provide a historical perspective of the discovery of endocannabinoid signalling and summarize the most recent findings on the role of endocannabinoids in the regulation of intracellular metabolism and its implications for whole-body homeostasis.
Article
Full-text available
The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket but that WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3 lysine. The Huffman laboratory identified strategies to establish CB2 receptor selectivity among cannabimimetic indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as “Alkyl Indole” receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB1 receptor have found their way into the market as “Spice” or “K2”. The sale of these alleged “herbal products” evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines.
Article
Full-text available
Studies on cannabinoids that predate the identification of ∆ ⁹ -THC as the intoxicating constituents of recreational cannabis by Raphael Mechoulam in 1964 are reviewed, critically analyzing the controversies and faux pas that have characterized the early research in this area. Significant contributions to the elucidation of the signature molecular scaffold of cannabinoids were provided by some of the finest organic chemists of their generation, like Roger Adams and the Nobel laureate Alexander Todd, and important studies of preeminent scientists like Robert Sidney Cahn and František Šantavý also deserve mentioning. The results of these studies include the structure elucidation of cannabinol ( 2a ), and the preliminary structure elucidation of cannabidiol (CBD, 3a ) and various semi-synthetic tetrahydrocannabinols (THCs). A comparative analysis of the contributions to the area by Adams and Todd highlights the transition between two generations of organic chemists, and the profound influence that the development of chromatographic methods of purification and of spectroscopic techniques of structure elucidation have played on the development of organic chemistry.
Chapter
Since antiquity, Cannabis has provoked enormous intrigue for its potential medicinal properties as well as for its unique pharmacological effects. The elucidation of its major cannabinoid constituents, Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), led to the synthesis of new cannabinoids (termed synthetic cannabinoids) to understand the mechanisms underlying the pharmacology of Cannabis. These pharmacological tools were instrumental in the ultimate discovery of the endogenous cannabinoid system, which consists of CB1 and CB2 cannabinoid receptors and endogenously produced ligands (endocannabinoids), which bind and activate both cannabinoid receptors. CB1 receptors mediate the cannabimimetic effects of THC and are highly expressed on presynaptic neurons in the nervous system, where they modulate neurotransmitter release. In contrast, CB2 receptors are primarily expressed on immune cells. The endocannabinoids are tightly regulated by biosynthetic and hydrolytic enzymes. Accordingly, the endocannabinoid system plays a modulatory role in many physiological processes, thereby generating many promising therapeutic targets. An unintended consequence of this research was the emergence of synthetic cannabinoids sold for human consumption to circumvent federal laws banning Cannabis use. Here, we describe research that led to the discovery of the endogenous cannabinoid system and show how knowledge of this system benefitted as well as unintentionally harmed human health.
Chapter
The diverse ways of obtaining 167 hydroxy-ketones and derivatives are described. Characterization data: Chemical name, Chemical Abstracts Service Registry Number (CAS-RN), molecular formula, molecular weight, spectroscopic data references, physico-chemical properties.
Chapter
The diverse ways of obtaining 718 hydroxy-ketones and derivatives are described. Characterization data: Chemical name, Chemical Abstracts Service Registry Number (CAS-RN), molecular formula, molecular weight, spectroscopic data references, physico-chemical properties.
Chapter
The diverse ways of obtaining 268 hydroxy-ketones and derivatives are described. Characterization data: Chemical name, Chemical Abstracts Service Registry Number (CAS-RN), molecular formula, molecular weight, spectroscopic data references, physico-chemical properties.
Chapter
The diverse ways of obtaining 319 hydroxy-ketones and derivatives are described. Characterization data: Chemical name, Chemical Abstracts Service Registry Number (CAS-RN), molecular formula, molecular weight, spectroscopic data references, physico-chemical properties.
Chapter
H. v. Pechman found that coumarin derivatives are formed when malic acid or beta-ketonic esters are condensed with phenols in the presence of concentrated sulfuric acid. This reaction is commonly known s the Pechmann reaction. It has found extensive use. Simonis and co-workers used phosphorus pentaoxide as the condensing agent in place of sulfuric acid and demonstrated that with the same reactants chromones rather than coumarins resulted. The condensation of a phenol and beta-ketonic ester in the presence of phosphorus pentaoxide is sometimes called the Simonis reaction, but it is actually a variation of the Pechmann reaction and is considered in this chapter. Other condensing agents that have been used, for example, are phosphorus oxychloride, phosphoric acid, zinc chloride and others. These are discussed in the chapter. By condensing appropriately substituted phenols and beta-ketonic esters, coumarins can be synthesized with substituents either in the benzene nucleus in the heterocyclic ring or both. The course of this reaction depends on three factors; nature of the phenol, of the beta-ketonic ester, and the condensing agent. Keywords: Pechmann reaction; malic acid; phenols; ketonic esters; 5-hydroxycoumarin derivatives; aluminum chloride; condensing agents; experimental procedures
Article
In this decade, classical cannabinoid SAR has increasingly been interpreted in terms of ligand-receptor interaction. Membrane receptor binding affinity, inhibition of receptor coupled processes, functional in vitro assays that distinguish between agonists and antagonists, transfected receptor systems, and distinction among receptor subtypes have been applied to cannabinoid pharmacology studies. These studies have revealed information about the pivotal receptor interaction that mediates the neurochemical system characterized by the receptor. The positive correlation between binding affinity and behavioral effects validates ligand-receptor interaction as a focus for developing new cannabinoids with the potential for selective pharmacological effects. Added to these direct receptor studies are the computational methods that compare active and inactive ligands for steric, electronic, and conformational similarities that reveal an SAR for activity with a sophistication and a perspective not possible before computer methodology. Merging these studies with knowledge of the receptor sequence, consequences of mutations of the receptor, and a calculated structure of the receptor are evolving a physical picture of the interaction of cannabinoids with its receptor(s). This picture of a ligand-receptor interaction guides medicinal chemists in their interpretation of classical cannabinoid SAR and the design of new analogs for selective pharmacological activity and as probes of the cannabinoid receptor. It is from a receptor perspective that this review of the SAR of classical cannabinoids is presented.
Article
A method is given for partially purifying the phenolic components of Cannabis sativa resin and for separating these components by means of paper chromatography. The application of this method for the preparation of pure cannabinol and tetrahydrocannabinol is described.
Article
New types of selective estrogen receptor modulators (SERMs) were synthesized and evaluated for their binding affinity and biological effect on reproductive cells. A proposed lead structure (B) was derivatized to provide compounds 30 and 44, which showed good estrogen-receptor binding affinity (K(i) values: 6.3 and 10 nM, respectively), as well as minimal impact on mammary and uterine carcinoma cells. Introduction of an alkyl group in the core structure considerably enhanced receptor-binding affinity of the compounds tested. Synthesis and structure-activity relationships of these compounds are described.
ResearchGate has not been able to resolve any references for this publication.