Thioformaldehyde S-Sulfide, Sulfur Analogue of the Criegee Intermediate: Structures, Energetics, and Rovibrational Analysis.

The ephemeral Criegee intermediate, first postulated over 70 years ago, has only recently been isolated in the gas phase. The sulfur analogue of this canonical zwitterion, thioformaldehyde S-sulfide, has eluded similar analysis; however, argon matrix isolation has been achieved ( Angew. Chem., Int. Ed. 2001 , 40 , 393 - 396 ). Here thioformaldehyde S-sulfide and its valence isomer dithiirane are examined with high-level coupled-cluster methods, including the minimum-energy pathway for interconversion. Relative enthalpies calculated from extrapolated energies at the complete basis set limit of the full CCSDTQ method are reported. Isomerization from thioformaldehyde S-sulfide to the lower-lying dithiirane (-7.2 kcal mol-1) is predicted to include a 27.0 kcal mol-1 barrier. Harmonic and anharmonic vibrational frequencies are also predicted using second-order vibrational perturbation theory. These results should aid in future gas-phase identification.

Substituted methcathinones differ in transporter and receptor interactions.

The use of synthetic methcathinones, components of "bath salts," is a world-wide health concern. These compounds, structurally similar to methamphetamine (METH) and 3,4-methylendioxymethamphetamine (MDMA), cause tachycardia, hallucinations and psychosis. We hypothesized that these potentially neurotoxic and abused compounds display differences in their transporter and receptor interactions as compared to amphetamine counterparts. 3,4-Methylenedioxypyrovalerone and naphyrone had high affinity for radioligand binding sites on recombinant human dopamine (hDAT), serotonin (hSERT) and norepinephrine (hNET) transporters, potently inhibited [³H]neurotransmitter uptake, and, like cocaine, did not induce transporter-mediated release. Butylone was a lower affinity uptake inhibitor. In contrast, 4-fluoromethcathinone, mephedrone and methylone had higher inhibitory potency at uptake compared to binding and generally induced release of preloaded [³H]neurotransmitter from hDAT, hSERT and hNET (highest potency at hNET), and thus are transporter substrates, similar to METH and MDMA. At hNET, 4-fluoromethcathinone was a more efficacious releaser than METH. These substituted methcathinones had low uptake inhibitory potency and low efficacy at inducing release via human vesicular monoamine transporters (hVMAT2). These compounds were low potency (1) h5-HT(1A) receptor partial agonists, (2) h5-HT(2A) receptor antagonists, (3) weak h5-HT(2C) receptor antagonists. This is the first report on aspects of substituted methcathinone efficacies at serotonin (5-HT) receptors and in superfusion release assays. Additionally, the drugs had no affinity for dopamine receptors, and high-nanomolar to mid-micromolar affinity for hSigma1 receptors. Thus, direct interactions with hVMAT2 and serotonin, dopamine, and hSigma1 receptors may not explain psychoactive effects. The primary mechanisms of action may be as inhibitors or substrates of DAT, SERT and NET.

Time-dependent negative reinforcement of ethanol intake by alleviation of acute withdrawal.

BACKGROUND: Drinking to alleviate the symptoms of acute withdrawal is included in diagnostic criteria for alcoholism, but the contribution of acute withdrawal relief to high alcohol intake has been difficult to model in animals. METHODS: Ethanol dependence was induced by passive intragastric ethanol infusions in C57BL/6J (B6) and DBA/2J (D2) mice; nondependent control animals received water infusions. Mice were then allowed to self-administer ethanol or water intragastrically. RESULTS: The time course of acute withdrawal was similar to that produced by chronic ethanol vapor exposure in mice, reaching a peak at 7 to 9 hours and returning to baseline within 24 hours; withdrawal severity was greater in D2 than in B6 mice (experiment 1). Postwithdrawal delays in initial ethanol access (1, 3, or 5 days) reduced the enhancement in later ethanol intake normally seen in D2 (but not B6) mice allowed to self-infuse ethanol during acute withdrawal (experiment 2). The postwithdrawal enhancement of ethanol intake persisted over a 5-day abstinence period in D2 mice (experiment 3). D2 mice allowed to drink ethanol during acute withdrawal drank more ethanol and self-infused more ethanol than nondependent mice (experiment 4). CONCLUSIONS: Alcohol access during acute withdrawal increased later alcohol intake in a time-dependent manner, an effect that may be related to a genetic difference in sensitivity to acute withdrawal. This promising model of negative reinforcement encourages additional research on the mechanisms underlying acute withdrawal relief and its role in determining risk for alcoholism.