Structure-Activity Relationships, Deuteration, and Fluorination of Synthetic Cannabinoid Receptor Agonists Related to AKB48, 5F-AKB-48, and AFUBIATA.

Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an -alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular -alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common.

Anion Architecture Controls Structure and Electroresponsivity of Anhalogenous Ionic Liquids in a Sustainable Fluid.

Three nonhalogenated ionic liquids (ILs) dissolved in 2-ethylhexyl laurate (2-EHL), a biodegradable oil, are investigated in terms of their bulk and electro-interfacial nanoscale structures using small-angle neutron scattering (SANS) and neutron reflectivity (NR). The ILs share the same trihexyl(tetradecyl)phosphonium ([P]) cation paired with different anions, bis(mandelato)borate ([BMB]), bis(oxalato)borate ([BOB]), and bis(salicylato)borate ([BScB]). SANS shows a high aspect ratio tubular self-assembly structure characterized by an IL core of alternating cations and anions with a 2-EHL-rich shell or corona in the bulk, the geometry of which depends upon the anion structure and concentration.

Lipid exchange of apolipoprotein A-I amyloidogenic variants in reconstituted high-density lipoprotein with artificial membranes.

High-density lipoproteins (HDLs) are responsible for removing cholesterol from arterial walls, through a process known as reverse cholesterol transport. The main protein in HDL, apolipoprotein A-I (ApoA-I), is essential to this process, and changes in its sequence significantly alter HDL structure and functions. ApoA-I amyloidogenic variants, associated with a particular hereditary degenerative disease, are particularly effective at facilitating cholesterol removal, thus protecting carriers from cardiovascular disease.

Small-Angle Neutron Scattering Insights into 2-Ethylhexyl Laurate: A Remarkable Bioester.

Commercial (protiated) samples of the "green" and biodegradable bioester 2-ethylhexyl laurate (2-EHL) were mixed with D-2-EHL synthesized by hydrothermal deuteration, with the mixtures demonstrating bulk structuring in small-angle neutron scattering measurements. Analysis in a polymer scattering framework yielded a radius of gyration () of 6.5 Å and a Kuhn length (alternatively described as the persistence length or average segment length) of 11.

High-Density Lipoprotein function is modulated by the SARS-CoV-2 spike protein in a lipid-type dependent manner.

There is a close relationship between the SARS-CoV-2 virus and lipoproteins, in particular high-density lipoprotein (HDL). The severity of the coronavirus disease 2019 (COVID-19) is inversely correlated with HDL plasma levels. It is known that the SARS-CoV-2 spike (S) protein binds the HDL particle, probably depleting it of lipids and altering HDL function.

Deuteration for biological SANS: Case studies, success and challenges in chemistry and biology.

Small angle neutron scattering is a powerful complementary technique in structural biology. It generally requires, or benefits from, deuteration to achieve its unique potentials. Molecular deuteration has become a mature expertise, with deuteration facilities located worldwide to support access to the technique for a wide breadth of structural biology and life sciences.

Selective Oxidations Using a Cytochrome P450 Enzyme Variant Driven with Surrogate Oxygen Donors and Light.

Cytochrome P450 monooxygenase enzymes are versatile catalysts, which have been adapted for multiple applications in chemical synthesis. Mutation of a highly conserved active site threonine to a glutamate can convert these enzymes into peroxygenases that utilise hydrogen peroxide (H O ). Here, we use the T252E-CYP199A4 variant to study peroxide-driven oxidation activity by using H O and urea-hydrogen peroxide (UHP).

The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist.

The development of selective CB receptor agonists is a promising therapeutic approach for the treatment of inflammatory diseases, without CB receptor mediated psychoactive side effects. Preliminary structure-activity relationship studies on pyrazoylidene benzamide agonists revealed the -ylidene benzamide moiety was crucial for functional activity at the CB receptor. A small library of compounds with varying linkage moieties between the pyrazole and substituted phenyl group has culminated in the discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist 19 (CBR EC = 19 nM, CBR EC > 10 μM).

An overview of late-stage functionalization in today's drug discovery.

: Late-stage functionalization (LSF) can introduce important chemical groups in the very last steps of the synthesis. LSF has the potential to speed up the preparation of novel chemical entities and diverse chemical libraries and have a major impact on drug discovery. Functional group tolerance and mild conditions allows access to new molecules not easily accessible by conventional approaches without the need for laborious chemical synthesis.

Strategies to develop selective CB receptor agonists from indole carboxamide synthetic cannabinoids.

Activation of the CB receptor is an attractive therapeutic strategy for the treatment of a wide range of inflammatory diseases. However, receptor subtype selectivity is necessary in order to circumvent the psychoactive effects associated with activation of the CB receptor. We aimed to use potent, non-selective synthetic cannabinoids designer drugs to develop selective CB receptor agonists.

Acute and residual effects in adolescent rats resulting from exposure to the novel synthetic cannabinoids AB-PINACA and AB-FUBINACA.

Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with ∆-tetrahydrocannabinol (THC) and control treatments.

Pharmacology of Indole and Indazole Synthetic Cannabinoid Designer Drugs AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, and 5F-ADBICA.

Synthetic cannabinoid (SC) designer drugs based on indole and indazole scaffolds and featuring l-valinamide or l-tert-leucinamide side chains are encountered with increasing frequency by forensic researchers and law enforcement agencies and are associated with serious adverse health effects. However, many of these novel SCs are unprecedented in the scientific literature at the time of their discovery, and little is known of their pharmacology. Here, we report the synthesis and pharmacological characterization of AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, 5F-ADBICA, and several analogues.