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. All synthesized SCs acted as high potency agonists of CB1 (EC50 = 0.24-21 nM) and CB2 (EC50 = 0.88-15 nM) receptors in a fluorometric assay of membrane potential, with 5F-ADB-PINACA showing the greatest potency at CB1 receptors. The cannabimimetic activities of AB-FUBINACA and AB-PINACA in vivo were evaluated in rats using biotelemetry. AB-FUBINACA and AB-PINACA dose-dependently induced hypothermia and bradycardia at doses of 0.3-3 mg/kg, and hypothermia was reversed by pretreatment with a CB1 (but not CB2) antagonist, indicating that these SCs are cannabimimetic in vivo, consistent with anecdotal reports of psychoactivity in humans.

Introduction: 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 de novo chemical synthesis. Areas Covered: A historical overview of late-stage functionalization and its applicability to drug discovery is provided. Pioneering methodologies that laid the foundations for the field are briefly covered and archetypal examples of their application to drug discovery are discussed. Novel methodologies reported in the past few years mainly stemming from the recent renaissances of photoredox catalysis and radical chemistry are reviewed and their application to drug discovery considered. Expert opinion: It is envisioned that late-stage functionalization will improve the efficiency and efficacy of drug discovery. There is evidence of the widespread uptake of LSF by the medicinal chemistry community and it is expected that the recent and continuing endeavors of many academic laboratories and pharmaceutical companies will soon have an impact on drug development.

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Cordiachromes A-F are terpenoid benzoquinones isolated from the heartwood of Cordia milenii. Cordiachrome C (3; R = H ) has a benzogeijerene and A (1 ; R = H) and B ( 2 ; R = H ) have a benzocogeijerene skeleton.Cordiachromes D-F are methoxy-derivatives of A-C, respectively. All six are optically inactive. Biogenetically they appear to be related to alkannin, which occurs in the same family (Boraginaceae). The distribution of cordiachromes in other Cordia spp. is surveyed CORDIA (Boraginaceae) is a genus of tropical trees, some of which yield valuable timber, but little is known of the wood extractives other than the presence of sesquiterpenes in C. trichotoma2 and C. chac~ensis.~ From the heartwood of C. millenii we have now isolated six terpenoid benzoquinones, cordiachromes A-F.* We have also examined sixteen other Cordia spp. (see Table ) ; all six pigments were found in C. goeldiana and C. platythyrsa, and cordiachromes A, B, and C in several other spp., but half of those examined contained no quinones a t all. Most of the structural work was carried out on cordiachrome B and this is discussed first. This is a 2,3-dialkylbenzoquinone showing 250 and 350 nm, vmax. 1650 and 1600 cm-l, and 7 3-30 (2H, s) ; it has typical redox properties, gives a positive Craven test, and forms a leucodiacetate. As the molecular formula is C1,H1802 the molecule must contain a benzoquinone ring fused to a CloHl, system containing three double-bond equivalents. That one of these is a terminal methylene group is evident from the formation of formaldehyde on ozonolysis, a strong i.r. band at 918 cm-l, and broad singlets (each 1H) in the n.m.r. spectrum at T 5-27 and 5-62. All of these signals disappear on hydrogenation, which gives (after reoxidation with silver oxide) a dihydro-derivative. In the absence of further unsaturation the CL0HlG system must comprise two rings, most probably in linear array Cordiachrome I?.

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IT has been suggested1 that tingenone, an orange pigment found in the bark of Euonymus tingens Wall., is a naphthoquinone. If so the intense visible absorption [ A, , , . 425 nm (log E 4-1 1) f ] is highly anomalous but would be consistent with certain quinone methide structures such as pristimerin (I; R = Me) [423 nm (log E 4-10)] and fuerstione (11) [445 nm (log E 4-09)]. Pristimerin (I ; R = Me), and also celastrol (I; R = H),4 occur in the bark and roots of several plants of the Celastraceae family to which Euonymus belongs. Direct comparison of the electronic spectra of tingenone and pristimerin showed that they were identical. Furthermore, the two n.m.r. t Not log E 5.02, which was based on an incorrect molecular

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 (H2O2). Here, we use the T252E‐CYP199A4 variant to study peroxide‐driven oxidation activity by using H2O2 and urea‐hydrogen peroxide (UHP). We demonstrate that the T252E variant has a higher stability to H2O2 in the presence of substrate that can undergo carbon‐hydrogen abstraction. This peroxygenase variant could efficiently catalyse O‐demethylation and an enantioselective epoxidation reaction (94 % ee). Neither the monooxygenase nor peroxygenase pathways of the P450 demonstrated a significant kinetic isotope effect (KIE) for the oxidation of deuterated substrates. These new peroxygenase variants offer the possibility of simpler cytochrome P450 systems for selective oxidations. To demonstrate this, a light driven H2O2 generating system was used to support efficient product formation with this peroxygenase enzyme.

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. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB-FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 × 1 mg/kg and 6 × 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1α and IL-12 were reduced by AB-FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation.