Francis E. Soroko

Bupropion hydrochloride ((±) α-t-butylamino-3-chloropropiophenone HCl): a novel antidepressant agent

Tricyclic compounds such as amitriptyline and related substances are considered to be clinically effective antidepressant agents (Kuhn, 1958; Hollister, 1972) with a mode of action dependent on the inhibition of the neuronal reuptake of one or more biogenic amine transmitters in the central nervous system (Glowinski & Axelrod, 1964). The tricyclics have not proved to be ideal agents in treating depression due to their slow OllSet of action, cholinolytic side effects, interactions with pressor amines and monoamine oxidase inhibitors and also due to a tendency to elicit cardiac arrhythmias Or standstill (Jefferson, 1975). Monoamine oxidase inhibitors are likewise considered to be effective antidepressant agents (American Psychiatric Association, 1974) which act by inhibiting intraneuronal monoamine Omdase in the central nervous system (cns). However, the currently available inhibitors also inhibit monow e oxidase in the liver and the ingestion of phenethylamine-type pressor substances in the diet, ‘WY an event made innocuous with the effective of the amines by liver monoamine oxidase, Correspondence. may lead to hypertensive crisis (Marley & Blackwell, 1970). We therefore sought an agent that would be active in antidepressant screening models, but differ chemically and pharmacologically from the tricyclics, and not be sympathomimetic, cholinolytic nor an inhibitor of monoamine oxidase. Bupropion (Wellbatrin) which was synthesized by one of the authors (N.B.M.) (Baltzly & Mehta, 1968; Mehta, 1974, 1975) meets these criteria and has the following structure:

Pro-convulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy

The pro-convulsant actions of theophylline and caffeine have been investigated using the hippocampal slice preparation and rats administered kainic acid or Metrazol. Both theophylline and caffeine induced the generation of epileptiform activity in the CA3 region of the hippocampal slice with convulsive dose50 (CD50) values of 3 microM respectively. Kainic acid-induced bursting in hippocampal slices was enhanced by theophylline (0.3-30 microM) and caffeine (1-100 microM). Theophylline induced burst firing in response to electrical stimulation in hippocampal area CA3 but not area CA1. Theophylline (50 mg/kg) strongly potentiated the effect of the limbic convulsant kainic acid in vivo whilst a dose of 200 mg/kg was necessary to significantly lower the threshold dose of Metrazol required to induce generalized convulsions. We conclude that alkylxanthines, probably by antagonizing the effect of endogenous adenosine, exert a pro-convulsant action in the hippocampus which preferentially promotes limbic seizures.

Anorexic effects of ethanolamine-O-sulfate and muscimol in the rat: evidence that GABA inhibits ingestive behavior.

Abstract Intracisternal injections of ethanolamine-O-sulfate (EOS), an irreversible selective inhibitor of GABA-transaminase (GABA-T), resulted in relatively long lasting dose dependent decreases in food consumption and body weight of rats. The anorexic effects of EOS generally corresponded in both time course and magnitude to the elevation of GABA levels and associated decreases in GABA-T activity. Chronic treatment with very high intraperitoneal doses of EOS which were able to cross the blood-brain barrier elevated GABA levels and resulted in weight loss. Muscimol, a GABA receptor agonist also produced anorexia. These findings are consistent with the view that GABA may be involved in mediation of satiety in the rat.

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.

Pharmacological Properties of 403U76, a New Chemical Class of 5-Hydroxytryptamine- and Noradrenaline-reuptake Inhibitor

403U76 (5‐chloro‐[[2‐[(dimethylamino)methyl]phenyl]thio]benzene‐methanol hydrochloride) is a potent, competitive, inhibitor of 5‐hydroxytryptamine (5‐HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5‐HT uptake in‐vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5‐hydroxytryptophan in rats and mice and blockade of p‐induced depletion of 5‐HT in rats.

Synthesis and evaluation of the anticonvulsant activity of a series of 2-amino-1-phenyl-1-propanols derived from the metabolites of the antidepressant bupropion

Abstract A series of 2-amino-1-phenyl-1-propanols that are structurally related to known metabolites of bupropion,1 (Wellbutrin®) were synthesized and evaluated as potential anticonvulsants. The ( R ∗ ,R ∗ )-2-tert- butylamino -1-(3- trifluoromethylphenyl ) propanol 20 had an ED50 of 16.5 ± 2.8 mg/kg ip in mice in the maximal electroshock screen and was chosen for further evaluation.

A Novel Inhibitor of Gamma-Aminobutyrate Aminotransferase with Anorectic Activity

Abstract: 1‐(n‐decyl)‐3‐Pyrazolidinone (BW357U) is a potent, selective inhibitor of gamma‐aminobutyrate aminotransferase (GABA‐T) in vitro and in vivo. After acute or chronic, oral or intraperitoneal administration of BW357U to rats, brain GABA levels were elevated in a dose‐dependent manner. When inhibition of brain GABA‐T exceeded 50%, whole brain GABA levels were elevated approximately threefold, and an anorectic effect was observed in the absence of other symptoms. This compound, because of its potency and selectivity, may be useful in studies relating to the function of GABA‐containing neurons in appetite regulation.

A role for GABA in the control of ingestive behavior in rats: Effects of ethanolamine-O-sulfate and muscimol

Abstract Ethanolamine-O-sulfate (EOS) is an irreversible selective inhibitor of GABA-transaminase. Intracisternal injections of EOS (100–400 μg/brain) produced dose-related inhibition of food-motivated operant behavior, decreases in food consumption and body weight, inhibition of GABA-transaminase, and increases in brain GABA levels. The time course of the changes in brain GABA correlated with the alterations in food-related behaviors. EOS over the same dose range did not produce observable changes in behavior, changes in operant behavior not motivated by food, or produce a conditioned taste aversion. Although EOS crosses the blood-brain barrier poorly, repeated intraperitoneal injections of 250 and 500 mg/kg produced decreases in body weight and increases in brain GABA levels. Confirmation of a role for GABA was obtained in experiments using aminooxyacetic acid, another GABA transaminase inhibitor, and muscimol, a GABA receptor agonist. These results suggest that a prominent pharmacological effect of GABA receptor stimulation and elevation of whole brain GABA is anorexia indicating that this putative neurotransmitter has a function in regulating hunger (or satiety) in the rat.

Synthesis and anticonvulsant activity of a series of benzamides

Summary A series of benzamides containing N,N,2-trimethyl-1,2-propane diamine as the amide moiety was synthesized. The compounds were evaluated in the maximal electroshock (MES) and pentylenetetrazol (metrazole, MET) screens for anticonvulsant activity. The 3,5-trifluoromethyl, 3,5-dichloro, and 3-bromo analogues proved to be either equipotent with or more potent than phenytoin.

Models of Depression Used in the Pharmaceutical Industry

An animal model is a representation of some aspects of a human disease. Modeling mental disease is problematic in that the symptoms may be poorly defined and the underlying pathophysiology poorly understood. This is especially true of depression, which is the name given to a heterogeneous group of disorders having in common the disturbance of mood (Cronholm, 1984; Klerman, 1984; Baldessarini, 1985). Models of depression are made primarily for two reasons: to allow experimental manipulation of behavioral and biochemical variables that might provide insight into the etiology and underlying pathophysiology of the disease and to allow prediction of how a variable such as an antidepressant drug might affect the disease (Everitt and Keverne, 1979).