Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand–receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure–activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.

The antiviral efficacies and cytotoxicities of 2,3-and 4-substituted 2,3-didehydro-2,3-dideoxycytidine analogs were evaluated. All compounds were tested (i) against a wild-type human immunodeficiency virus type 1 (HIV-1) isolate (strain xxBRU) and lamivudine-resistant HIV-1 isolates, (ii) for their abilities to inhibit hepatitis B virus (HBV) production in the inducible HepAD38 cell line, and (

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Enantiomeric synthesis of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus are described. The key intermediate (-)- and (+)-cyclopentenyl alcohols (7 and 15) were prepared from D-gamma-ribonolactone and D-ribose, respectively. Coupling of 7 with appropriately blocked purine and pyrimidine bases via the Mitsunobu reaction followed by deprotection afforded the target L-(+)-cyclopentenyl nucleosides (24-28, 31, 33, and 36). D-(-)-Cyclopentenyl nucleosides (1, 40, 43, and 52-56) were also prepared by a similar procedure for L-isomers from 15. The synthesized compounds were evaluated for their antiviral activity against two RNA viruses: HIV and West Nile virus. Among the synthesized D-(-)-nucleosides, adenine (1, neplanocin A), cytosine (55, CPE-C), and 5-fluorocytosine (56) analogues exhibited moderate to potent anti-HIV activity (EC(50) 0.1, 0.06, and 5.34 microM, respectively) with significant cytotoxicity in PBM, Vero, and CEM cells. Also, cytosine (55) and 5-fluorocytosine (56) analogues exhibited the most potent anti-West Nile virus activity (EC(50) 0.2-3.0 and 15-20 microM, respectively). Among L-(+)-nucleosides, only the cytosine (27) analogue exhibited weak anti-HIV activity (EC(50) 58.9 microM).

The recent outbreak of severe acute respiratory syndrome (SARS), which is an acute respiratory illness, is caused by newly discovered SARS coronavirus (SARS-CoV). Herein we describe the antiviral activity of several classes of nucleoside analogues evaluated against SARS-CoV in Vero 76 cells, some of which exhibited moderate activity.

Quercetin-amino acid conjugates with alanine or glutamic acid moiety attached at 7-O and/or 3-O position of quercetin were prepared, and their multidrug resistance (MDR)-modulatory effects were evaluated. A quercetin-glutamic acid conjugate, 7-O-Glu-Q (3a), was as potent as verapamil in reversing MDR and sensitized MDR MES-SA/Dx5 cells to various anticancer drugs with EC50 values of 0.8-0.9 μM. Analysis on Rh-123 accumulation confirmed that 3a inhibits drug efflux by Pgp, and Pgp ATPase assay showed that 3a interacts with the drug-binding site of Pgp to stimulate its ATPase activity. Physicochemical analysis of 3a revealed that solubility, stability, and cellular uptake of quercetin were significantly improved by the glutamic acid promoiety, which eventually dissociates from 3a to produce quercetin and quercetin metabolites in intracellular milieu. Taken together, potent MDR-modulating activity along with intracellular conversion into the natural flavonoid quercetin warrants development of the quercetin-amino acid conjugates as safe MDR modulators.

In this study, as a bioisosteric alternative scaffold of the antiviral aryl diketoacids (ADKs), we used 5-hydroxychromone on which two arylmethyloxy substituents were installed. The 5-hydroxychromones (5b-5g) thus prepared showed anti-HCV activity and, depending on the aromatic substituents on the 2-arylmethyloxy moiety, some of the derivatives (5b-5f) were also active against SCV. In addition, unlike the ADKs which showed selective inhibition against the helicase activity of the SCV NTPase/helicase, the 5-hydroxychromones (5b-5f) were active against both NTPase and helicase activities of the target enzyme. Among those, 3-iodobenzyloxy-substituted derivative 5e showed the most potent activity against HCV (EC(50) = 4 μM) as well as SCV (IC(50) = 4 μM for ATPase activity, 11 μM for helicase activity) and this might be used as a platform structure for future development of the multi-target or broad-spectrum antivirals.

5-HTR2A is involved in melanogenesis. These findings highlight the role of 5-HT and suggest new ways of controlling melanogenesis.