Dual-use nano-neurotechnology.

The chemical and biological nonproliferation regime stands at a watershed moment, when failure seems a real possibility. After the unsuccessful outcome of the 2016 Eighth Review Conference, the future of the Biological and Toxin Weapons Convention is uncertain. As the Chemical Weapons Convention (CWC) approaches its Fourth Review Conference in 2018, it has almost completed removing the huge stocks of chemical weapons, but it now faces the difficult organizational task of moving its focus to preventing the reemergence of chemical weapons at a time when the international security situation appears to be increasingly more difficult and dangerous. In this article, we assess the current and near-term state (5-10 years) and impact of three related areas of science and technology that could be of dual-use concern: targeted delivery of agents to the central nervous system (CNS), particularly by means of nanotechnology; direct impact of nanomaterials on synaptic functions in the CNS; and neuronal circuits in the brain that might be targeted by those with hostile intent. We attempt to assess the implications of our findings, particularly for the consideration of the problem of state-level interest in so-called nonlethal incapacitating chemical agents for law enforcement at the CWC Review Conference in 2018, but also more generally for the longer-term future of the chemical and biological nonproliferation regime.

Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system.

The endocannabinoid system (ECS) represents one of the major neuromodulatory systems involved in different physiological and pathological processes. Multi-target compounds exert their activities by acting via multiple mechanisms of action and represent a promising pharmacological modulation of the ECS. In this work we report 4-substituted and 4,5-disubstituted 1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives with a broad spectrum of affinity and functional activity towards both cannabinoid receptors and additional effects on the main components of the ECS. In particular compound B3 showed high affinity for CB1R (Ki = 23.1 nM, partial agonist) and CB2R (Ki = 6.9 nM, inverse agonist) and also significant inhibitory activity (IC50 = 70 nM) on FAAH with moderate inhibition of ABHD12 (IC50 = 2.5 µΜ). Compounds B4, B5 and B6 that act as full agonists at CB1R and as partial agonists (B5 and B6) or antagonist (B4) at CB2R, exhibited an additional multi-target property by inhibiting anandamide uptake with sub-micromolar IC50 values (0.28-0.62 µΜ). The best derivatives showed cytotoxic activity on U937 lymphoblastoid cells. Finally, molecular docking analysis carried out on the three-dimensional structures of CB1R and CB2R and of FAAH allowed to rationalize the structure-activity relationships of this series of compounds.

2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain.

2-Arachidonoylglycerol (2-AG) is a signaling lipid in the central nervous system that is a key regulator of neurotransmitter release. 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. It is involved in a wide array of (patho)physiological functions, such as emotion, cognition, energy balance, pain sensation and neuroinflammation. In this review, we describe the biosynthetic and metabolic pathways of 2-AG and how chemical and genetic perturbation of these pathways has led to insight in the biological role of this signaling lipid. Finally, we discuss the potential therapeutic benefits of modulating 2-AG levels in the brain.

The Therapeutic Aspects of the Endocannabinoid System (ECS) for Cancer and their Development: From Nature to Laboratory.

The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids' mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field.

Palmitoylethanolamide: problems regarding micronization, ultra-micronization and additives.

It can be established that at least two of the writers of the article published in 'Inflammopharmacology', title: 'Palmitoylethanolamide (PEA), a naturally occurring disease-modifying agent in neuropathic pain' have a direct connection to the companies Epitech and Innovet. These companies produce micronized and ultra-micronized PEA. Therefore it is of eminent importance to determine whether the statements in this paper have also taken into consideration the European guidelines for Good Clinical Practice and the codes of good scientific practices. This is very questionable. A minimum condition in clinical studies for proving the claim that PEA in its micronized and ultra-micronized formulations works better than in its pure form or in other formulations is that a comparison be made between: PEA in pure form or in other formulations, on the one hand; PEA in the micronized and ultra-micronized formulations, on the other hand. This minimum condition is not complied with. Based on additional studies discussed in this commentary and in view of the effects of ultra-micronization on the parameters discussed, as well as the potential side-effects of additives such as excipients and herbal extracts added to the products cited in the article, the preference should be for the time being to treat patients with pure PEA without any of these additives.

No more pain upon Gq-protein-coupled receptor activation: role of endocannabinoids.

Marijuana has been used to relieve pain for centuries. The analgesic mechanism of its constituents, the cannabinoids, was only revealed after the discovery of cannabinoid receptors (CB1 and CB2) two decades ago. The subsequent identification of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and their biosynthetic and degradation enzymes discloses the therapeutic potential of compounds targeting the endocannabinoid system for pain control. Inhibitors of the anandamide and 2-AG degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase, respectively, may be superior to direct cannabinoid receptor ligands as endocannabinoids are synthesized on demand and rapidly degraded, focusing action at generating sites. Recently, a promising strategy for pain relief was revealed in the periaqueductal gray (PAG). It is initiated by Gq-protein-coupled receptor (Gq PCR) activation of the phospholipase C-diacylglycerol lipase enzymatic cascade, generating 2-AG that produces inhibition of GABAergic transmission (disinhibition) in the PAG, thereby leading to analgesia. Here, we introduce the antinociceptive properties of exogenous cannabinoids and endocannabinoids, involving their biosynthesis and degradation processes, particularly in the PAG. We also review recent studies disclosing the Gq PCR-phospholipase C-diacylglycerol lipase-2-AG retrograde disinhibition mechanism in the PAG, induced by activating several Gq PCRs, including metabotropic glutamatergic (type 5 metabotropic glutamate receptor), muscarinic acetylcholine (M1/M3), and orexin 1 receptors. Disinhibition mediated by type 5 metabotropic glutamate receptor can be initiated by glutamate transporter inhibitors or indirectly by substance P, neurotensin, cholecystokinin and capsaicin. Finally, the putative role of 2-AG generated after activating the above neurotransmitter receptors in stress-induced analgesia is discussed.

4-Aminocyclopentane-1,3-diols as platforms for diversity: synthesis of anandamide analogs.

Starting from cyclopentadiene, two racemic mixtures of 4-aminocyclopentane-1,3-diols were prepared in 8 steps and characterized. Structure determination proved the anticipated trans-orientation of the two oxygen atoms with respect to the plane of the ring. The fragment-like new compounds are small and hydrophilic, devoid of rotatable bonds, and offer stereochemically defined attachment points for substituents. Thus, these platforms for diversity are suitable starting points for the construction of combinatorial libraries of lead-like 4-amidocyclopentane-1,3-diols or natural product analogs. As a proof of concept, cyclopentanoid anandamide analogs were prepared using these molecular platforms and evaluated as tools for the investigation of unresolved issues in the molecular biology of anandamide.

Spice drugs: los cannabinoides como nuevas drogas de diseño / Spice drugs: cannabinoids as a new designer drugs

Desde 2004 se venden en Internet y tiendas especializadas (smart shops) algunos preparados conteniendo mezclas de hierbas para fumar con la marca de Spice drugs. Estos productos se publicitan como una mezcla exótica de incienso aromático y se especifica que no son aptos para uso humano. Muchos usuarios, tras consumir estos productos fumados, refieren que sus efectos son similares a los del cannabis. Los preparados Spice drugs se han hecho muy populares en los foros de Internet sobre drogas ya que podrían representar la posibilidad de obtener un sustituto legal del cannabis. Los análisis forenses de algunos de estos preparados encontraron la presencia de agonistas cannabinoides sintéticos muy potentes como el JWH-018, CP 47497, JWH-073 y HU-210. Hay muy pocos datos sobre sus propiedades farmacológicas en animales y ninguno sobre su toxicidad. En la actualidad, no se sabe casi nada sobre su farmacología, toxicología y seguridad en humanos, si exceptuamos las opiniones de los consumidores en Internet. Ni los ingredientes vegetales, ni ninguno de los cannabinoides encontrados se hallan en las listas de sustancias controladas de las convenciones de 1961 o 1971 de la ONU. Recientemente, algunos países han emprendido acciones legales para prohibir o controlar los preparados Spice drugs y similares. Estos cannabinoides pueden considerarse nuevas sustancias a añadir a la lista de drogas de diseño (AU)

Some smokable herbal mixtures under the brand name Spice drugs have been sold on the Internet and in specialised shops (smart shops) since 2004. The mixtures are advertised as an exotic incense blend which releases a rich aroma and not for human consumption. When smoked, Spice drugs products have been reported by some users to have effects similar to those of cannabis. Spice drugs have received intensive attention in drug forums due to the possibility to obtain a non legal substitute of cannabis. Forensic analyses have found different potent synthetic cannabinoid agonists in some Spice drugs products, as JWH-018, CP 47497, JWH-073 and HU-210. There are few data about its pharmacological properties in animals, but nothing about its toxicity. At present, almost nothing is known about the pharmacology, toxicology and safety profile of such compounds in humans, except the opinions of consumers in internet forums. Neither the herbal ingredients of Spice drugs, nor any of the synthetic cannabinoids found in them, are internationally controlled under the 1961 or 1971 UN drug control conventions. Some European countries have recently taken legal actions to ban or otherwise control Spice drugs products and related compounds. These cannabinoid substances can be considered as new products to be added to the list of “designer drugs (AU)