|Nature. 2017 Jul 5. doi: 10.1038/nature23272. [Epub ahead of print]|
Crystal structures of agonist-bound human cannabinoid receptor CB1.
Hua T1,2,3, Vemuri K4, Nikas SP4, Laprairie RB5, Wu Y1, Qu L1,2,3, Pu M1, Korde A4, Jiang S4, Ho JH5, Han GW6, Ding K1,3,7, Li X8, Liu H8, Hanson MA9, Zhao S1,7, Bohn LM5, Makriyannis A4, Stevens RC1,6,7, Liu ZJ1,2,7.
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Center for Drug Discovery, Department of Pharmaceutical Sciences; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA.
Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Complex Systems Division, Beijing Computational Science Research Center, Beijing 100193, China.
GPCR Consortium, San Marcos, California 92078, USA.
The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist ?9-tetrahydrocannabinol (?9-THC). Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80?Å and 2.95?Å resolution, respectively. The two CB1-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe2003.36 and Trp3566.48 (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of ?9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.
[and this..... "CB2 antagonism increased seizure severity"...... ??]
Epilepsia. 2017 Jul 10. doi: 10.1111/epi.13842. [Epub ahead of print]
Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats.
Huizenga MN1, Wicker E1, Beck VC1, Forcelli PA1,2,3.
Pharmacology & Physiology, Georgetown University, Washington, District of Columbia, U.S.A.
Neuroscience, Georgetown University, Washington, District of Columbia, U.S.A.
Interdisciplinary Program in Neuroscience, Georgetown University, Washington, District of Columbia, U.S.A.
Although drugs targeting the cannabinoid system (e.g., CB1 receptor agonists) display anticonvulsant efficacy in adult animal models of seizures/epilepsy, they remain unexplored in developing animal models. However, cannabinoid system functions emerge early in development, providing a rationale for targeting this system in neonates. We examined the therapeutic potential of drugs targeting the cannabinoid system in three seizure models in developing rats.
Postnatal day (P) 10, Sprague-Dawley rat pups were challenged with the chemoconvulsant methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) or pentylenetetrazole (PTZ), after treatment with either CB1/2 mixed agonist (WIN 55,212-2), CB1 agonist (arachidonyl-2'-chloroethylamide [ACEA]), CB2 agonist (HU-308), CB1 antagonist (AM-251), CB2 antagonist (AM-630), fatty acid amide hydrolase inhibitor (URB-597), or G protein-coupled receptor 55 agonist (O-1602). P20 Sprague-Dawley pups were challenged with DMCM after treatment with WIN, ACEA, or URB. Finally, after pretreatment with WIN, P10 Sprague-Dawley rats were challenged against acute hypoxia-induced seizures.
The mixed CB1/2 agonist and the CB1-specific agonist, but no other drugs, displayed anticonvulsant effects against clonic seizures in the DMCM model. By contrast, both CB1 and CB2 antagonism increased seizure severity. Similarly, we found that the CB1/2 agonist displayed antiseizure efficacy against acute hypoxia-induced seizures (automatisms, clonic and tonic-clonic seizures) and tonic-clonic seizures evoked by PTZ. Anticonvulsant effects were seen in P10 animals but not P20 animals.
Early life seizures represent a significant cause of morbidity, with 30-40% of infants and children with epilepsy failing to achieve seizure remission with current pharmacotherapy. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority. These data indicate that the anticonvulsant action of the CB system is specific to CB1 receptor activation during early development and provide justification for further examination of CB1 receptor agonists as novel antiepileptic drugs targeting epilepsy in infants and children.
[and just parking this.....]
Drug Test Anal. 2017 Jul 3. doi: 10.1002/dta.2237. [Epub ahead of print]
Structural characterization and pharmacological evaluation of the new synthetic cannabinoid 'CUMYL-PEGACLONE'.
Angerer V1,2, Mogler L1,2, Steitz JP3, Bisel P3, Hess C4, Schoeder CT5, Müller CE5, Huppertz LM1, Westphal F6, Schäper J7, Auwärter V1.
Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Hermann Staudinger Graduate School, University of Freiburg, Freiburg, Germany.
Institute for Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany.
Institute of Forensic Medicine, Forensic Toxicology, University of Bonn, Bonn, Germany.
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
State Bureau of Criminal Investigation Schleswig-Holstein, Kiel, Germany.
State Bureau of Criminal Investigation Bavaria, München, Germany.
The number of new psychoactive substances (NPS) that have emerged on the European market has been rapidly growing in the last years, with a particularly high number of new compounds from the group of synthetic cannabinoid receptor agonists. There have been various political efforts to control the trade and the use of NPS worldwide. In Germany, the 'Act to control the distribution of new psychoactive substances' (NpSG) came into force in November 2016. In this new Act two groups of substances were defined, the group 'cannabimimetics/synthetic cannabinoids' covering indole, indazole and benzimidazole core structures, and a second group named 'compounds derived from 2-phenethylamine'. Shortly after, the first retailers of 'herbal blends' promoted new products allegedly not violating the German NpSG. We describe the identification and structural elucidation 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. For isolation of the substance a flash chromatography separation was applied. The structure elucidation was performed using gas chromatography-mass spectrometry (GC-MS), gas chromatography-solid state infrared spectroscopy (GC-sIR), liquid chromatography-electrospray ionization-quadrupole time of flight-mass spectrometry (LC-ESI-qToF-MS) and nuclear magnetic resonance (NMR) analysis. Additionally, binding affinity towards the cannabinoid receptors CB1 and CB2 and efficacy in a cAMP accumulation assay was measured, showing full agonistic activity and high potency at both receptors. The new compound bears a ?-carboline core structure circumventing the German NpSG and also the generic definitions in other national laws. As a semi-systematic name for 2-cumyl-5-pentyl-gamma-carbolin-1-one CUMYL-PEGACLONE is suggested.