Pharmacology and Mechanism of Action of HSK16149, a Selective Ligand of α2δ Subunit of Voltage-Gated Calcium Channel with Analgesic Activity in Animal Models of Chronic Pain.

Chronic pain is a public health problem because current treatments are unsatisfactory with small therapeutic index. Although pregabalin is effective for treating chronic pain, the clinical use is limited because of its side effects. Therefore, improving its therapeutic index is essential. In this study, HSK16149 was found to be a novel ligand of voltage-gated calcium channel (VGCC) α 2 δ subunit. HSK16149 inhibited [3H]gabapentin binding to the α 2 δ subunit and was 23 times more potent than pregabalin. In two rat models of neuropathic pain, the minimum effective dose (MED) of HSK16149 was 10 mg/kg, and the efficacy was similar to that of 30 mg/kg pregabalin. Moreover, the efficacy of HSK16149 could persist up to 24 hours postadministration at 30 mg/kg, whereas the efficacy of pregabalin lasted only for 12 hours at 30 mg/kg in streptozotocin-induced diabetic neuropathy model, indicating that HSK16149 might be a longer-acting drug candidate. HSK16149 could also inhibit mechanical allodynia in intermittent cold stress model and decrease phase II pain behaviors in formalin-induced nociception model. In addition, the locomotor activity test showed that the MED of HSK16149 was similar to that of pregabalin, whereas in the Rotarod test, the MEDs of HSK16149 and pregabalin were 100 and 30 mg/kg, respectively. These findings indicated that HSK16149 might have a better safety profile on the central nervous system. In summary, HSK16149 is a potent ligand of VGCC α 2 δ subunit with a better therapeutic index than pregabalin. Hence, it could be an effective and safe drug candidate for treating chronic pain. SIGNIFICANCE STATEMENT: As a novel potent ligand of voltage-gated calcium channel α 2 δ subunit, HSK16149 has the potential to be an effective and safe drug candidate for the treatment of chronic pain.

A fractional phase-coding strategy for terahertz beam patterning on digital metasurfaces.

Coding metasurfaces have drawn great attention for its digital wave manipulation in deep subwavelength-scale in the last decade, more sophisticated and flexible coding strategies suitable for terahertz wavefront manipulations are becoming more urgently demanded. Due to its rigidity in phase gradient division, both phase gradient metasurfaces and conventional phase coding technique lack the flexibility to expand applications in a large field of view and accurate targeting. This study presents a generalized coding method by precisely reconfiguring the array factor based on the phased array theory and metasurface concept, which can be applied for anomalous scattering and ultrafine radiation patterning. According to our quantitative analysis on the relationship between the deflected angles and the supercell spacing, a fractional coding method for arbitrary phase gradient distribution has been attained by logically discretizing the spacing scale of supercells. By switching on different coding sequences or incident frequencies, a single beam to multiple beam scanning in an expanded angular range with minimal step can be achieved on the fractional phase-coding metasurfaces. As a proof of concept, the 2-bit coding metasurfaces arranged by four fractional coding sequences have been fabricated and measured, demonstrating a consecutive single-beam steering pattern ranging from 22° to 74° in 0.34-0.5 THz. Crosswise verified by the good accordance among numerical prediction, simulation and experiment, the proposed coding strategy paves a path to delicate beam regulation for high-resolution imaging and detection.

Dual-band refractometric terahertz biosensing with intense wave-matter-overlap microfluidic channel.

We theoretically and experimentally demonstrate a label-free terahertz biosensor with ultrahigh sensitivity and distinctive discretion. By constructing a metal-air-metal (MAM) metamaterial perfect absorber (MPA) with a metallic paired-ring resonator array, a hollow microfluidic channel, and a backed reflector, a novel dual-band absorptive sensing platform is proposed in the THz range. The near field coupling by dipole-induced trapped modes and the magnetic momentum caused a vertical to transverse power flux that dramatically enhanced the electromagnetic field on top of the metasurface and in the microfluidic channel, respectively. Both the resonant modes exhibit perfect absorption and produce ultrahigh normalized sensitivities of 0.47/RIU (refractive index unit, RIU) and 0.51/RIU at 0.76 THz and 1.28 THz, respectively. Compared with conventional microfluidic sensors, the salient advantages of our design are the perfect spatial overlap for light-matter interaction and polarization insensitivity. Characterized by THz time domain spectroscopic absorption quantification measurements with different concentrations of bovine serum albumin (BSA), the proposed sensor exhibits promising applications in microfluidic biosensing.

Discovery of a Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor (HSK0935) for the Treatment of Type 2 Diabetes.

A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.

Terahertz dual-resonance bandpass filter using bilayer reformative complementary metamaterial structures.

A dual-resonance frequency selective surface filter in the THz range that uses bilayer modified complementary metamaterial structures is proposed in this Letter. The bandpass filter, with dual bands centered at 0.315 and 0.48 THz, uses a single crystal quartz substrate and is simulated, fabricated, and measured. To minimize the manufacturing risks of working with fragile and thin quartz substrates, efforts have been made to improve the transmission frequency response features at realizable substrate thicknesses. Experimental results from 0.1 to 0.6 THz measured by THz time-domain spectroscopy show excellent agreement with the simulation results.

One-pot synthesis of benzo[f]quinolin-3-ones and benzo[a]phenanthridein-5-ones by the photoanuulation of 6-chloropyridin-2-ones and 3-chloroisoquinolin-1-ones to phenylacetylene.

The one-pot synthesis of benzo[f]quinolin-3-ones and benzo[a]phenanthridein-5-ones was achieved by the inter- and intramolecular photoannulation of 6-chloropyridin-2-ones and 3-chloroisoquinolin-1-ones with phenylacetylene or tethered phenylacetylene. The reactions were proceeded by photoaddition of 6-chloropyridin-2-ones and 3-chloroisoquinolin-1-ones to phenylacetylene to give the chlorine-substituted stilbenoids, and then 6π electrocyclization of the stilbenoids and oxidation aromatization to afford the polycyclic products.

Photoinduced cyclization of 3-acyl-2-halo-1-[(ω-phenylethynyl)alkyl]indoles to azaheterocyclo[1,2,3-lm]-fused benzo[c]carbazoles.

A one-pot synthesis of azaheterocyclo[1,2,3-lm]-fused benzo[c]carbazoles (2 and 3) has been developed by photocyclization of 3-acyl-2-halo-1-[(ω-phenylethynyl)alkyl] indoles (1) in good to excellent yields. All products are formed from 1 via two sequential photocyclization reactions. Two products, 9-chloro-7,8-dihydro-6H-benzo[c]pyrido[1,2,3-lm]carbazole (2a-h) and 7,8-dihydro-6H-benzo[c]pyrido[1,2,3-lm]carbazole (3a-h), are produced in the photocyclization of 2-halo-1-[(ω-phenylethynyl)alkyl]indole-3-carbaldehydes (1a-h). In contrast, only products 2a-h are produced in the photocyclization of 3-acetyl-2-chloro-1-[(ω-phenylethynyl)alkyl]indole-3-carbaldehydes (1o-t). The 9-H in 3a-h (n = 2) does originate from the formyl group in 1a-h via 1,5-hydrogen shift. The structures of three new products, 9-bromo-7,8-dihydro-6H-benzo[c]pyrido[1,2,3-lm]carbazole (2b), 9-chloro-10-methyl-7,8-dihydro-6H-benzo[c]pyrido[1,2,3-lm]carbazole (3h) and 12-chloro-7,8-dihydro-6H-benzo[c]pyrido[1,2,3-lm]carbazole (2w), have been corroborated by single-crystal X-ray structural analyses.

CuI-catalyzed photochemical or thermal reactions of 3-(2-azidobenzylidene)lactams. Application to the synthesis of fused indoles.

Photochemical or thermal reactions of 3-(2-azidobenzylidene)-lactams afforded fused indoles such as indolo[3,2-c]quinolin-6-ones, pyrido[4,3-b]indol-1-ones and other similar compounds in moderate to high yields via cyclization-ring expansion reactions. The photolytic process was much more facile than the thermal process and could be further improved by addition of CuI.

Photoinduced Intramolecular addition of 3-acyl-2-haloindoles to alkenes.

1,2-Fused indoles and pyrroles were prepared via an efficient intramolecular photoaddition reaction of 1-(omega-alkenyl)-2-haloindole-3-carbaldehydes and 1-(omega-alkenyl)-2-chloropyrrole-3-carbaldehydes. The presence of an acyl group was necessary for the photocyclization reactions. The halogen-atom-retained exo- and endo-cyclization products were generally produced with results similar to those of an atom-transfer cyclization reaction. In contrast, unsaturated cyclization products were obtained in the photoreaction of substrates having methyl groups on the vinyl group.

One-pot synthesis of benzo[c]carbazoles by photochemical annulation of 2-chloroindole-3-carbaldehydes.

A novel and efficient procedure for the synthesis of benzo[c]carbazoles has been achieved in moderate to high yields by the one-pot photochemical annulations of 2-chloroindole-3-carbaldehydes by styrenes via photodechlorination-initiated coupling of 2-chloroindole-3-carbaldehydes with styrenes, electrocyclic reactions and deformylative aromatization in the presence of pyridine.