Structural modifications to an N-methyl-D-aspartate receptor antagonist result in large differences in trapping block.

Differences in the degree of trapping of initial block by N-methyl-D-aspartate (NMDA) receptor antagonists may affect their safety and, hence, suitability for clinical trials. In this comparative study, 23 compounds structurally related to the low-affinity, use-dependent NMDA receptor antagonist (S)-alpha-phenyl-2-pyridineethanamine dihydrochloride (AR-R15896AR) were examined to determine the degree of trapping block they exhibit. Compounds were tested at concentrations that produced a comparable initial 80% block of NMDA-mediated whole-cell current in rat cortical cultures. A wide range of values of trapping block was found, indicating that trapping is not an all-or-none event. Fifteen of the compounds trapped significantly more than the 54 +/- 3% of initial block trapped by AR-R15896AR. The off-rates of these compounds were slower than that of AR-R15896AR. Only 2 of the 23 compounds trapped significantly less than AR-R15896AR. AR-R15808, the piperidine analog of AR-R15896AR, appeared to trap only 8 +/- 3% of its initial block, although its fast off-rate confounded accurate quantification of trapping. AR-R26952, which, like AR-R15896AR, contains a pyridine in place of a phenyl group, trapped 40 +/- 5% of its initial block and exhibited kinetics comparable with AR-R15896AR. Structure-activity analysis suggested that the presence of two basic nitrogen atoms and decreased hydrophobicity led to decreased trapping. There was no correlation between trapping and lipophilicity as would be expected if closed-channel egress was due to escape through the lipid bilayer. However, there was a positive correlation between off-rate and degree of trapping. Models that can account for partial trapping are presented.

Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives.

Two new series of antitumor agents, 4-aminomethylthioxanthenones (6-50) and 5-aminomethylbenzothiopyranoindazoles (51-61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48-50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.

Chemoreceptors in lepidoptera: stereochemical differentiation of dual receptors for an achiral pheromone.

The racemate and optically pure enantiomers of 9-(2-cyclopenten-1yl)nonyl acetate have been synthesized and shown to mimic certain biological properties of (Z)-11-tetradecenyl acetate. European corn borers and red-banded leaf rollers respond differently to the racemate and to the enantiomers in precopulatory behavior bioassay. The responses demonstrate the presence of two stereospecific chemoreceptors, show the chiral character of these receptors, and define the conformation of carbon atoms 10 to 14 of (Z)-11-tetradecenyl acetate in these receptors.

Insect sex pheromones: minor amount of opposite geometrical isomer critical to attraction.

(Z)-II-Tetradecenyl acetate is the reported sex pheromone of European corn borer and redbanded leafroller moths. However, geometrically pure preparations of the compound are weakly attractive to these species. Presence of the E geometrical isomer in the Z is necessary for maximum sex attraction and these moths are "tuned" to respond optimally to specific proportions of Z to E. This discovery is important to considerations of moth pheromonal specificity, evolution, and in application of knowledge of the pheromones to insect-pest suppression.