Adding more "Spice" to the pot; a review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists.

  title={Adding more "Spice" to the pot; a review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists.},
  author={Ryan M Alam and John J. Keating},
  journal={Drug testing and analysis},
Synthetic cannabinoid receptor agonists (SCRAs) first appeared on the international recreational drug market in the early 2000s in the form of SCRA-containing herbal blends. Due to the cannabimimetic effects associated with the consumption of SCRAs, they have acquired an ill-informed reputation for being cheap, safe, and legal alternatives to illicit cannabis. Possessing high potency and affinity for the human cannabinoid receptor subtype-1 (CB1 ) and -2 (CB2 ), it is now understood that the… 
Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling
Various cell-based assay technologies are being utilized to develop structure versus activity relationships (SAR) for the SCs and to explore the effects of these compounds on noncannabinoid receptor targets, which focuses on describing and evaluating these assays and summarizes current knowledge of SC molecular pharmacology.
Synthetic Cannabinomimetics: A Brief History and the Challenges They Pose for the Forensic Chemist
Since the first detection of synthetic cannabinomimetics in herbal smoking blends in 2008 the clandestine production of these compounds, based on seizure data, increased in number every year until
Exploring Stereochemical and Conformational Requirements at Cannabinoid Receptors for Synthetic Cannabinoids Related to SDB-006, 5F-SDB-006, CUMYL-PICA, and 5F-CUMYL-PICA.
Molecular dynamics simulations provided a conformational basis for the observed differences in agonist potency at CB1 pending benzylic substitution, highlighting an enantiomeric bias for this series of SCRAs.
Defining Steric Requirements at CB1 and CB2 Cannabinoid Receptors Using Synthetic Cannabinoid Receptor Agonists 5F-AB-PINACA, 5F-ADB-PINACA, PX-1, PX-2, NNL-1, and Their Analogues.
In vitro binding affinities and functional activities at cannabinoid type 1 and 2 receptors (CB1 and CB2, respectively) were determined for all the library members using radioligand competition experiments and a fluorescence-based membrane potential assay, providing insights regarding structural contributions to the cannabimimetic profiles of 17, 18, 19, and 20.
Clinical and Forensic Toxicological Aspects of Synthetic Cannabinoids: A Narrative Review and Update
  • Medicine
  • 2020
Like natural cannabinoids, the SCs abuse/poisoning has serious and life-threatening effects in abuser and suitable measures for information to the public and health care professionals for prevention of SCs Abuse are recommended.
The endocannabinoid system – current implications for drug development
  • C. Fowler
  • Biology, Medicine
    Journal of internal medicine
  • 2020
In this review, the state of the art for compounds affecting the endocannabinoid (eCB) system is described with a focus on the treatment of pain and dual‐acting compounds targeting this enzyme and other targets such as cyclooxygenase‐2 or transient potential vanilloid receptor 1 may be a way forward for the Treatment of pain.
Synthesis and in Vitro Cannabinoid Receptor 1 Activity of Recently Detected Synthetic Cannabinoids 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA.
This study confirms that recently detected SCRAs 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-Pica, CUMYL-CBMICA, ADB-BINACA, APP-BinACA, 4F and 5F were all able to activate the CB1 receptor in vitro, albeit to different extents, and are potentially psychoactive in vivo.
Psychotomimetic symptoms after a moderate dose of a synthetic cannabinoid (JWH-018): implications for psychosis
It is suggested that a moderate dose of JWH-018 induces pronounced psychotomimetic symptoms in healthy participants with no history of mental illness, which confirms that SCs pose a serious risk for public health.
Synthetic cannabinoid receptor agonists: analytical profiles and development of QMPSB, QMMSB, QMPCB, 2F-QMPSB, QMiPSB, and SGT-233.
Six SCRAs carrying the quinolin-8-yl ester head group were extensively characterized and may be useful to researchers and scientists who deal with the emergence of NPS during forensic and clinical investigations.
A Comparison of Acute Neurocognitive and Psychotomimetic Effects of a Synthetic Cannabinoid and Natural Cannabis at Psychotropic Dose Equivalence
It is concluded that psychotropic dose equivalence provides a uniform approach for comparing the neurocognitive and psychotomimetic profiles of CB1 agonists, which can also be applied to other drug classes.


The Chemistry and Pharmacology of Synthetic Cannabinoid Receptor Agonist New Psychoactive Substances: Evolution.
This chapter will chart the evolution of recently identified SCRA NPS chemotypes, as well as their putative manufacturing by-products and thermolytic degradants, and describe structure-activity relationships within each class.
Pharmacological evaluation of synthetic cannabinoids identified as constituents of spice
Evaluated a large series of heterocyclic compounds, 1,3-disubstituted indole and 2-azaindole derivatives known or assumed to be CB1 receptor agonists, many of which have previously been identified in forensic samples and investigated the activities of the compounds at the orphan G protein-coupled receptors GPR18 and GPR55 both of which are known to interact with cannabinoids.
Pharmacological evaluation of new constituents of “Spice”: synthetic cannabinoids based on indole, indazole, benzimidazole and carbazole scaffolds
All compounds showed high CB receptor selectivity, mostly interacting with both subtypes, CB1 and CB2, and will be useful to assess the compounds’ toxicological risks and to guide legislation.
Structural characterization and pharmacological evaluation of the new synthetic cannabinoid CUMYL-PEGACLONE.
The identification and structural elucidation is described of one of the first synthetic cannabinoids not being covered by the NpSG, 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one, showing full agonistic activity and high potency at both receptors.
Medicinal Use of Synthetic Cannabinoids—a Mini Review
All the issues related to their appropriate dosage, mode of action, acute and chronic effects in vivo, interaction with other drugs, their metabolism, etc. need much research to be done so that it will be easier to predict their different aspects in human subjects in more appropriate way.
Do toxic synthetic cannabinoid receptor agonists have signature in vitro activity profiles? A case study of AMB-FUBINACA.
A basic molecular pharmacology characterization of AMB-FUBINACA in comparison to traditional research cannabinoids CP55,940, WIN55,212-2, and Δ9-THC in fundamental pathways of receptor activity revealed that it is highly efficacious and potent in all pathways assayed.
Legal controls on cannabimimetics: an international dilemma?
  • L. King
  • Biology
    Drug testing and analysis
  • 2014
The growing interest in the clinical potential of tetrahydrocannabivarin (THCV) is inhibited, at least in the UK, by its unintended status as a Schedule 1 substance, and the generic definition of classical cannabinoids shows signs of weakness.
New Synthetic Cannabinoids Metabolism and Strategies to Best Identify Optimal Marker Metabolites
Current SC prevalence is reviewed, the necessity for SC metabolism investigation is established and the advantages and disadvantages of multiple metabolic approaches are compared, and a practical strategy to select optimal urinary marker metabolites for SCs is devised.