Morton Harfenist

BW234U,(cis-9-[3–(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride): a novel antipsychotic agent

The capacity of neuroleptic drugs to antagonize the behavioural effects of the dopamine agonist , apomorphine, in animals has been used as a basis for identifying new compounds with potential antipsychotic actions in man (Fielding & La1 1974). Experience has shown that neuroleptic drugs which are potent antagonists of apomorphine-induced stereotyped behaviour, produce a high incidence of extrapyramidal side effects and tardive dyskinesias in man (Niemegeers 1974; Berger et a1 1978). In addition to stereotyped behaviour, however, apomorphine produces other behavioural effects. Thus, McKenzie (1971) reported that apomorphine elicited fighting in paired male rats and Costall et a1 (1979) reported that apomorphine elicited climbing behaviour in mice. Both of these behavioural effects can be antagonized by neuroleptic drugs. These considerations led to the formulation of a research program which had as its goal the development of a compound that would (1) block apomorphine-induced aggression in rats and apomorphine-induced climbing in mice, but (2) not block stereotyped behaviour in either species. From a theoretical point of view climbing and aggressiveness produced by apomorphine probably reflect stimulation of dopamine receptors in the limbic system whereas stereotyped behaviour reflects stimulation of dopamine receptors in the striatum (Fielding & La1 1974; Costall et a1 1979; Costall & Naylor 1981). Overactivity of the limbic system has been implicated in the etiology of psychotic behaviour in man (Hokfelt et a1 1974). It was reasoned that a compound exhibiting selective blockade of climbing and aggressive behaviour would share with neuroleptic drugs the ability to influence cognitive and affective changes characteristic of psychosis, but unlike neuroleptic agents would not produce extrapyramidal side effects. The pharmacology of compound, BW 234U which evolved from this program, is presented below.

Biochemical and pharmacologic properties of 2614w94, a reversible, competitive inhibitor of monoamine oxidase-A

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.