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2614W94 [3-(1-trifluoromethyl)ethoxyphenoxathiin 10,10-dioxide] is a selective, reversible inhibitor of monoamine oxidase-A with a competitive mechanism of inhibition and a Ki value of 1.6 nM with serotonin as substrate. In pretreated rats, the ED50 value after single oral dosing was 1.7 mg/kg, similar to an ED50 value of 1.1 mg/kg estimated in the 5-hydroxytryptophan potentiation test. Maximal inhibition of monoamine oxidase-A (MAO-A) was observed by 0.5 h after dosing, suggesting rapid transport to brain. Inhibition in brain was maintained for several hours, followed by a gradual reversal with a half-time of 7.2 h. Brain levels of parent compound were higher than plasma levels at all times after dosing. No significant inhibition of MAO-B was observed. After preincubation of MAO with 2614W94 at 37°C, the inhibition was reversed by dialysis. Concentrations of serotonin, norepinephrine, and dopamine were clearly elevated in brains of rats after single oral doses, whereas levels of MAO metabolites were decreased. In a rat model designed to show blood pressure elevations in response to a threshold dose of orally administered tyramine, 2614W94 compared well with moclobemide, an MAO-A selective inhibitor that has not been associated with problems relating to dietary tyramine. The two stereoisomers of 2614W94 were both potent MAO-A inhibitors. In vitro and in vivo properties of 2614W94 suggest that this compound and its close analogs are among the most potent MAO-A inhibitors known and that they may have therapeutic potential as safe new antidepressant/anxiolytic agents. Drug Dev. Res. 45:1–9, 1998. © 1998 Wiley-Liss, Inc.

Extracts of Ginkgo biloba leaves produce reversible inhibition of rat brain monoamine (MAO). Both MAO-A and -B types were inhibited to a similar extent. The MAO inhibitory compound(s) were present in dried or fresh Ginkgo biloba leaves as well as in commercially available capsules of Ginkgo biloba and appear to be heat stable with relatively low molecular weight. MAO inhibition by Ginkgo biloba may be a mechanism underlying reported anti-stress and anxiolytic activities of this natural product.

BW 1370U87 is a potent, selective inhibitor of rat and human MAO-A with a competitive mechanism of action. Ki = 0.01 μM with either serotonin or tyramine as substrate. After preincubation of BW 1370U87 with mitochondrial MAO, full enzyme activity was restored by dialysis. Following oral administration to rats, BW 1370U87 inhibited brain MAO-A in a dose-dependent manner, with a duration greater than 6 hr, but less than 24 hr. No significant inhibition of MAO-B by BW 1370U87 was observed either in vitro or ex vivo. The selectivity, reversibility, and competitive kinetics of the inhibition by BW 1370U87 may contribute to an improved safety profile with this novel MAO-A inhibitor.

The activity of carnitine acetyltransferase (acetyl-CoA:L-carnitine O-acetyltransferase) was found to be at least 50-fold higher than that of choline acetyltransferase in PC12 cells. Nerve growth factor stimulated both enzymes in a parallel manner with respect to concentration of NGF and culture time. The stimulation of both enzymes was completely inhibited by 10 microM 6-thioguanine, an inhibitor of protein kinase N. Results are discussed with reference to the hypothesis that the two enzymes may be functionally related in neuronal cells.

Synthesis of [3H]acetylcholine from [3H]acetyl-L-carnitine was demonstrated in vitro by coupling the enzyme systems choline acetyltransferase and carnitine acetyltransferase. Likewise, both [3H] and [14C] labeled acetylcholine were produced when [3H]acetyl-L-carnitine and D-[U-14C] glucose were incubated with synaptosomal membrane preparations from rat brain. Transfer of the acetyl moiety from acetyl-L-carnitine to acetylcholine was dependent on concentration of acetyl-L-carnitine and required the presence of coenzyme A, which is normally produced as an inhibitory product of choline acetyltransferase. These results provide further evidence for a role of mitochondrial carnitine acetyltransferase in facilitating transfer of acetyl groups across mitochondrial membranes, thus regulating the availability in the cytoplasm of acetyl-CoA, a substrate of choline acetyltransferase. They are also consistent with a possible utility of acetyl-L-carnitine in the treatment of age-related cholinergic deficits.