Noel Michael Paul

The swift conversion of chemistry courses to various online formats has presented challenges for students and instructors alike, with one of the most significant challenges being the logistics concerning online testing. At our institution, instructors of general, organic, and physical chemistry courses sought to balance issues of exam access, exam security, and continuity with a traditional test format when switching to unproctored online exams. Different approaches were utilized for exam delivery with varying success. Common challenges arose in several courses, such as the need to train students to use new technology, and the threat of online information for compromising exam security. The most successful attempts to meet these challenges, such as use of a test-bank, are consistent with reported best practices and suggest a way to maximize access, security, and continuity, while working to diminish technological and ethical pitfalls that accompany unproctored online exams.

We probed tandem aldol condensations of sixteen o-hydroxyacetophenones, carrying electron withdrawing and donating groups at positions 4 and 5, by using five molar equivalents of SiCl4 in anhydrous ethanol. Substrates carrying moderate EWGs (0< >0.63) populated the equilibria with isospiropyrans (1274% yield), while those carrying strongly EDGs ( <0.31) gave flavylium salts (5080 %) or thermochromic bis-spiropyrans (73%). The results are of interest for developing novel organic materials possessing switchable photochromic and thermochromic characteristics.

Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss–Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000–10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [(±)-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.

Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; K_i(D2R/D3R) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2_LR- or hD3R-transfected HEK 293 cells (31, K_i(D2R/D3R) = 33.4:15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, K_i(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.

The synthesis and conformational properties of folded dendrons based on a 2-methoxyisophthalamide (2-OMe-IPA) repeat unit are described. The hydrodynamic properties of dendrons preorganized via the syn-syn conformational preference of 2-methoxyisophthalamide are compared with 2,6-pyridinedicarboxamide (2,6-pydic) analogues. The effect of subtle differences in the nature of the conformational equilibria that exist within the 2-OMe-IPA and 2,6-pydic repeat units on the global structural properties of the corresponding dendrons was explored computationally, by (1)H-DOSY NMR spectroscopy and time-resolved fluorescence anisotropy (TRFA) measurements. Whereas the syn-syn preference of the 2-OMe-IPA branched repeat unit is stabilized entirely by intramolecular hydrogen-bonding interactions, this preference in the 2,6-pydic system is a consequence of both intramolecular hydrogen-bonding and dipole minimization effects. However, nonspecific solvophobic compression is more important in determining hydrodynamic properties than solvent-dependent shifts in the conformational equilibria of the repeat unit for both dendron series.