Integration Analysis of miRNA Circulating Expression Following Cerebellar Transcranial Direct Current Stimulation in Patients with Ischemic Stroke.

The aim of this study was to explore the molecular mechanisms underlying cerebellar transcranial direct current stimulation (ctDCS) as a rehabilitation intervention for patients with ischemic stroke, focusing on the role of microRNAs (miRNAs). Whole-transcriptome sequencing was employed to obtain circulating expression profiles of miRNAs, long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and mRNAs in patients with ischemic stroke before and after 3-week ctDCS. miRanda software was used to predict the target genes of miRNAs, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to identify biological functions and signaling pathways.

5-Aryluracils as potent GnRH antagonists-Characterization of atropisomers.

Optimization of a series of uracils bearing a 2-fluoro- or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II.

Identification of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives as novel GnRH receptor antagonists.

A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats.

A thienopyridazinone-based melanin-concentrating hormone receptor 1 antagonist with potent in vivo anorectic properties.

Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration.

Substituted chromones and quinolones as potent melanin-concentrating hormone receptor 1 antagonists.

A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.

Synthesis and structure-activity relationships of biarylcarboxamide bis-aminopyrrolidine urea derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1).

A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.

Bis(aminopyrrolidine)-derived ureas (APUs) as potent MCH1 receptor antagonists.

Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).