The GluN2C subunit of the NMDA receptor is enriched in the neurons in the nucleus reticularis of the thalamus (nRT), but its role in regulating their function is not well understood. We found that deletion of GluN2C subunit did not affect spike frequency in response to depolarizing current injection or hyperpolarizationinduced rebound burst firing of nRT neurons. D-Cycloserine or CIQ (GluN2C/GluN2D positive allosteric modulator) did not affect the depolarization-induced spike frequency in nRT neurons. A newly identified highly potent and efficacious coagonist of GluN1/GluN2C NMDA receptors, AICP ((R)-2-amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid), was found to reduce the spike frequency and burst firing of nRT neurons in wild type but not GluN2C knockout. This effect was potentially due to facilitation of GluN2C-containing receptors, because inhibition of NMDA receptors by AP5 did not affect spike frequency in nRT neurons. We evaluated the effect of intracerebroventricular injection of AICP. AICP did not affect basal locomotion or prepulse inhibition but facilitated MK-801induced hyperlocomotion. This effect was observed in wildtype but not in GluN2C knockout mice, demonstrating that AICP produces GluN2C-selective effects in vivo. Using a chemogenetic approach, we examined the role of nRT in this behavioral effect. G q-or G i-coupled DREADDs were selectively expressed in nRT neurons using Cre-dependent viral vectors and PV-Cre mouse line. We found that similar to AICP effect, activation of G q-but not G i-coupled DREADD facilitated MK-801-induced hyperlocomotion. Together, these results identify a unique role of GluN2C-containing receptors in the regulation of nRT neurons and suggest GluN2C-selective in vivo targeting of NMDA receptors by AICP.

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We report the design, synthesis, and mechanistic study of a novel series of 2-piperazineone peptidomimetics as HIV capsid modulators by mimicking the structure of host factors binding to CA.

Lesinurad is a uricosuric agent for the treatment of hyperuricemia associated with gout, which was found lacking in efficacy and safety. Here, scaffold hopping and molecular hybridization were exploited to modify all the structural components of lesinurad, and 36 novel compounds bearing bicyclic imidazolopyridine core were obtained. In a mouse model of acute hyperuricemia, 29 compounds demonstrated increased serum uric acid (SUA)-reducing activity; SUA was treated with 12, 23, and 29 about fourfold lower compared with that of lesinurad. Moreover, 23 exhibited stronger URAT1 inhibition activity (IC50 = 1.36 μM) than lesinurad (IC50 = 5.54 μM). Additionally, 23 showed favorable safety profiles, and no obvious acute toxicity was observed in Kunming mice under a single dose of 1000 mg·kg–1. 23 also achieved excellent pharmacokinetic properties with the oral bioavailability of 59.3%. Overall, all the results indicated that 23 is a promising drug candidate in the treatment of hyperuricemia and gout.

HIV-1 capsid (CA) performs multiple roles in the viral life cycle and is a promising target for antiviral development. In this work, we describe the design, synthesis, assessment of antiviral activity, and mechanistic investigation of 20 piperazinone phenylalanine derivatives with a terminal indole or benzene ring. Among them, F2-7f exhibited moderate anti-HIV-1 activity with an EC50 value of 5.89 μM, which was slightly weaker than the lead compound PF74 (EC50 = 0.75 μM). Interestingly, several compounds showed a preference for HIV-2 inhibitory activity, represented by 7f with an HIV-2 EC50 value of 4.52 μM and nearly 5-fold increased potency over anti-HIV-1 (EC50 = 21.81 μM), equivalent to PF74 (EC50 = 4.16 μM). Furthermore, F2-7f preferred to bind to the CA hexamer rather than to the monomer, similar to PF74, according to surface plasmon resonance results. Molecular dynamics simulation indicated that F2-7f and PF74 bound at the same site. Additionally, we computationally analyzed the ADMET properties for 7f and F2-7f. Based on this analysis, 7f and F2-7f were predicted to have improved drug-like properties and metabolic stability over PF74, and no toxicities were predicted based on the chemotype of 7f and F2-7f. Finally, the experimental metabolic stability results of F2-7f in human liver microsomes and human plasma moderately correlated with our computational prediction. Our findings show that F2-7f is a promising small molecule targeting the HIV-1 CA protein with considerable development potential.

Globus pallidus externa (GPe) is a nucleus in the basal ganglia circuitry involved in the control of movement. Recent studies have demonstrated a critical role of GPe cell types in Parkinsonism. Specifically increasing the function of parvalbumin (PV) neurons in the GPe has been found to facilitate motor function in a mouse model of Parkinson’s disease (PD). The knowledge of contribution of NMDA receptors to GPe function is limited. Here, we demonstrate that fast spiking neurons in the GPe express NMDA receptor currents sensitive to GluN2C/GluN2D-selective inhibitors and glycine site agonist with higher efficacy at GluN2C-containing receptors. Furthermore, using a novel reporter model, we demonstrate the expression of GluN2C subunits in PV neurons in the GPe which project to subthalamic nuclei. GluN2D subunit was also found to localize to PV neurons in GPe. Ablation of GluN2C subunit does not affect spontaneous firing of fast spiking neurons. In contrast, facilitating the function of GluN2C-containing receptors using glycine-site NMDA receptor agonists, D-cycloserine (DCS) or AICP, increased the spontaneous firing frequency of PV neurons in a GluN2C-dependent manner. Finally, we demonstrate that local infusion of DCS or AICP into the GPe improved motor function in a mouse model of PD. Together, these results demonstrate that GluN2C-containing receptors and potentially GluN2D-containing receptors in the GPe may serve as a therapeutic target for alleviating motor dysfunction in PD and related disorders.