Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1,3)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor.

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 () as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation.

Intracellular Binding Site for a Positive Allosteric Modulator of the Dopamine D1 Receptor.

The binding site for DETQ [2-(2,6-dichlorophenyl)-1-((1,3)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1)-yl)ethan-1-one], a positive allosteric modulator (PAM) of the dopamine D1 receptor, was identified and compared with the binding site for CID 2886111 [-(6--butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide], a reference D1 PAM. From D1/D5 chimeras, the site responsible for potentiation by DETQ of the increase in cAMP in response to dopamine was narrowed down to the N-terminal intracellular quadrant of the receptor; arginine-130 in intracellular loop 2 (IC2) was then identified as a critical amino acid based on a human/rat species difference. Confirming the importance of IC2, a 2-adrenergic receptor construct in which the IC2 region was replaced with its D1 counterpart gained the ability to respond to DETQ.

Genetic assessment of Staphylococcus aureus in an underreported locality: Ambulatory care clinic.

Background: Staphylococcus aureus has strong association with anthropogenic environments. This association has not been well supported by use of genetic tools. The aim of this study was to phylogenetically relate numerous isolates from three environments - NCBI samples from hospitals, a community, and a previously unexplored healthcare environment: an ambulatory care clinic (ACC).

Rapid assessment of conformational preferences in biaryl and aryl carbonyl fragments.

The ability to rapidly assess the preferred conformation of key fragments in a structure "by visual inspection" is a very useful starting point in the process of drug design. With the ability to do so, one could address questions like: "How could we avoid planarity in a molecule?", "Will a molecule change its conformational preference if we make it more or less basic?" or "How does this electronic repulsion affect the conformational preference in the system?" in timely fashion. In this paper, we describe how the conformational energy profile (CEP, plot of energy as a function of dihedral bond angle) of a fragment can be interpreted through the understanding the interplay between resonance stabilization, steric effects and electrostatic interactions.

Cessation from Smoking Improves Innate Host Defense and Clearance of Experimentally Inoculated Nasal Staphylococcus aureus.

nasal carriage is transient in most humans and usually benign, but dissemination of to extranasal sites causes the majority of clinical infections, and is a major cause of serious infections in the United States. A better understanding of innate nasal decolonization mechanisms is urgently needed, as are relevant models for studying clearance. Here, we screened a population of healthy smokers for nasal carriage and compared the participants' abilities to clear experimentally applied nasal before and after completion of a smoking cessation program.