Overview of the CNS pharmacology of BW 1370U87: A chemically novel, reversible, selective MAO‐A inhibitor with potential to be a new antidepressant drug

Abstract

Kraemer, and R.M. Ferris: Overview of the CNS pharmacology of BW 137OU87: a chemically novel, reversible, selective MAO-A inhibitor with potential to be a new antidepressant drug. Drug Dev. Res. 25:181-190, 1992. BW 13701187 is a potent, reversible, selective inhibitor of rat and human brain MAO-A with a competitive mechanism of action. The E D , , of BW 13701187 for inhibition of MAO-A in rat brain is 8 mg/kg after oral administration, and the duration of action exceeds 7 hr. The ED, , dose for inhibition of MAO-A (20 mg/kg) elevates NE, DA, and 5-HT levels in brains of rats without significantly potentiating the blood pressure effects of a 15 rng/kg oral dose of tyramine. This dose of tyramine, extrapolated to man, exceeds the amount that could be consumed at one time from dietary sources. No inhibition of MAO-B has been observed with BW 13701187 either in vitro or ex vivo. BW 13701187 was effective in the 5-hydroxytryptophan potentiation test over the dose range that produced MAO-A inhibition in brain in both rats and mice, and it reduced swim stress induced immobility in the Porsolt test. The compound has positive effects on abnormal social behavior produced by early social deprivation in the rhesus monkey. BW 13701187 had no adverse cardiovascular effects in dogs or rats. It also had no significant pharmacological effects on various isolated tissue preparations and did not cause changes in the neuronal transport or the receptor systems which mediate the antidepressant effects or side effects of the tricyclic antidepressants. An acute oral dose 100 times that which produced an 80% inhibition of brain MAO-A exhibited no signs of toxicity. BW 137OU87 appears to be a safe reversible MAO-A inhibitor with potential for treating depression, anxiety conditions, panic, phobias, obsessive compulsive behaviors, and borderline personality disorders.

Inhibition of monoamine oxidase–A activity in rat brain by synthetic hydrazines: Structure-activity relationship (SAR)

“…It is considered that depression occurs as a result of functional deficiency of monoamines (viz 5-HT and NA) at neuronal levels [21,22]. It is also established that MAO inhibitors (both non-selective and selective) are used for the treatment of depression.…”

“…Similar to phenelzine, various anti-depressants e.g. MAOIs: clorgyline [21] and TCAs (tricyclic anti-depressants): imipramine have been reported to reduce locomotor activity due to somnolence or lowered muscle tone or both [16,17]. In the case of compound 1, the locomotor activity of animals remained unchanged up to the dose of 16 mg/kg but at higher dose (19 mg/kg), it produced a significant decline (30%) in motor performance of animals.…”

Selective Inhibitors of Monoamine Oxidase (MAO). 5. 1-Substituted Phenoxathiin Inhibitors Containing No Nitrogen That Inhibit MAO A by Binding It to a Hydrophobic Site

“…Compound 13 had an ED 80 of 8 mg/kg in inhibition of rat brain MAO A in vivo and was active in standard antidepressant models (Porsolt test in rats, potentiation of 5-HT activities in rats and mice, and a Rhesus model of borderline personality disorder). More comprehensive data on the pharmacology of 13 have been presented and published − (synonyms for 13 were 1370U and BW1370U87).…”

“…Compound 13 had an ED 80 of 8 mg/kg in inhibition of rat brain MAO A in vivo and was active in standard antidepressant models (Porsolt test in rats, potentiation of 5-HT activities in rats and mice, and a Rhesus model of borderline personality disorder). More comprehensive data on the pharmacology of 13 have been presented and published [11][12][13] (synonyms for 13 were 1370U and BW1370U87). The detected metabolites of 13 were found to be the vinyl analogue 22, the product of R hydroxylation 33, the acetyl compound 48, the product of β hydroxylation 42, the product of 1,2-dihydroxylation 44, and the carboxylic acid 54 produced by terminal oxidation of the ethyl group.…”