Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT Receptor Agonist.

Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT receptor agonist. CYB210010 exhibited high agonist potency at 5-HT and 5-HT receptors, modest selectivity over 5-HT, 5-HT, 5-HT, and adrenergic α receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.

SNARE Proteins in Synaptic Vesicle Fusion.

Neurotransmitters are stored in small membrane-bound vesicles at synapses; a subset of synaptic vesicles is docked at release sites. Fusion of docked vesicles with the plasma membrane releases neurotransmitters. Membrane fusion at synapses, as well as all trafficking steps of the secretory pathway, is mediated by SNARE proteins.

Interspecies complementation identifies a pathway to assemble SNAREs.

Unc18 and SNARE proteins form the core of the membrane fusion complex at synapses. To understand the functional interactions within the core machinery, we adopted an "interspecies complementation" approach in . Substitutions of individual SNAREs and Unc18 proteins with those from yeast fail to rescue fusion.

Synergistic interactions of repurposed drugs that inhibit Nsp1, a major virulence factor for COVID-19.

Nsp1 is one of the first proteins expressed from the SARS-CoV-2 genome and is a major virulence factor for COVID-19. A rapid multiplexed assay for detecting the action of Nsp1 was developed in cultured lung cells. The assay is based on the acute cytopathic effects induced by Nsp1.

Unc13 Aligns SNAREs and Superprimes Synaptic Vesicles.

Unc13 proteins are required for vesicle docking and priming during exocytosis. In this issue of Neuron, Lai et al. (2017) demonstrate that Unc13 ensures that the SNAREs assemble into functional subcomplexes.