Synthesis of a Tetrahydro­naph­thyridine Spiro­pyrimidine­trione DNA Gyrase Inhibiting Antibacterial Agent - Differential Substitution at all Five Carbon Atoms of Pyridine.

The synthesis of (−)-<b>1</b>, a potent antibacterial agent, was achieved stereoselectively in nine steps from readily available starting materials. Directed metalations were developed to assemble a pentasubstituted pyridine with appropriately positioned aldehyde and dimethylmorpholine substituents for a key tertiary amino effect reaction (T-reaction) that led to the spirocylic architecture. Ultimately, (−)-<b>1</b> was isolated as the thermodynamically most favored stereoisomer

Structures and Rotational Barriers of a Diiodobinorsnoutane: Energetic Preference for <i>Gauche</i> Conformation

The diiodobinorsnoutane, bi­(5-iodopentacyclo­[4.3.0.0^2,4.0^3,8.0^5,7]­non-4-yl) (<b>5</b>), exists in a sterically hindered <i>gauche</i> conformation rather than an <i>anti</i> or an averaged (freely rotating) <i>C</i>_2<i>v</i> structure. Density functional theory (DFT) predictions place the <i>gauche</i> conformation 11 kcal/mol more stable than the <i>anti</i> conformation with a barrier of 17 kcal/mol connecting the minima. These are consistent with variable-temperature NMR (17.1 ± 0.8 kcal/mol) estimates and X-ray analysis. Predictions of the torsional profiles of the yet-unsynthesized bromo-, chloro-, and fluoro- analogues show a progressive lowering of the barriers

Discovery and Preclinical Validation of [¹¹C]AZ13153556, a Novel Probe for the Histamine Type 3 Receptor

The histamine type 3 receptor (H₃) is a G protein-coupled receptor implicated in several disorders of the central nervous system. Herein, we describe the radiolabeling and preclinical evaluation of a candidate radioligand for the H₃ receptor, 4-(1<i>S</i>,2<i>S</i>)-2-(4-cyclobutylpiperazine-1-carbonyl)­cyclopropyl]-<i>N</i>-methyl-benzamide (<b>5</b>), and its comparison with one of the frontrunner radioligands for H₃ imaging, namely, GSK189254 (<b>1</b>). Compounds <b>1</b> and <b>5</b> were radiolabeled with tritium and carbon-11 for in vitro and in vivo imaging experiments. The in vitro binding of [³H]<b>1</b> and [³H]<b>5</b> was examined by (i) saturation binding to rat and nonhuman primate brain tissue homogenate and (ii) in vitro autoradiography on tissue sections from rat, guinea pig, and human brain. The in vivo binding of [¹¹C]<b>1</b> and [¹¹C]<b>5</b> was examined by PET imaging in mice and nonhuman primates. <i>B</i>_max values obtained from Scatchard analysis of [³H]<b>1</b> and [³H]<b>5</b> binding were in good agreement. Autoradiography with [³H]<b>5</b> on rat, guinea pig, and human brain slices showed specific binding in regions known to be enhanced in H₃ receptors, a high degree of colocalization with [³H]<b>1</b>, and virtually negligible nonspecific binding in tissue. PET measurements in mice and nonhuman primates demonstrated that [¹¹C]<b>5</b> binds specifically and reversibly to H₃ receptors in vivo with low nonspecific binding in brain tissue. Whereas [¹¹C]<b>1</b> showed similar binding characteristics in vivo, the binding kinetics appeared faster for [¹¹C]<b>5</b> than for [¹¹C]<b>1</b>. Conclusions: [¹¹C]<b>5</b> has suitable properties for quantification of H₃ receptors in nonhuman primate brain and has the potential to offer improved binding kinetics in man compared to [¹¹C]<b>1</b>

Azepines and Piperidines with Dual Norepinephrine Dopamine Uptake Inhibition and Antidepressant Activity

Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, <b>8b</b> and <b>21a</b>, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay