Relationship between the ability of some neuroleptics to enhance striatal [3H]dopamine release and their lipophilicity.

The ability of micromolar concentrations (100 microM) of some neuroleptics to enhance release of [3H]dopamine from rat striatum was studied. All the neuroleptics tested potentiated [3H]dopamine release, the most potent being chlorpromazine, prochlorperazine and fluphenazine and the least potent being sulpiride and metoclopramide. Apomorphine did not reverse the effects of fluphenazine and the stereo-isomers of flupenthixol were almost equipotent. These results indicated a direct, non-receptor, mediated mechanism. The lipophilicity of the neuroleptics, determined by reversed-phase TLC, showed a good correlation with their ability to enhance dopamine release. It is concluded that the lipophilicity of these drugs is partly responsible for the enhanced release of dopamine and may be clinically important following chronic administration of neuroleptics.

Potentiation of LON 954 tremor by typical and atypical neuroleptics--an indication of striatal dopamine antagonism.

Tremor produced in laboratory mice by the benzylimidoylurea derivative LON 954 was potentiated in a dose-dependent manner by a variety of typical and atypical neuroleptics. The most effective agents in this respect were those shown by other workers to have a selective action at dopamine receptors, notably the butyrophenones, thioxanthines and fluphenazine. Chlorpromazine and prochlorperazine produced inconsistent effects while clozapine and loxapine respectively delayed and prolonged the peak tremor response. While these findings support primary involvement of striatal dopaminergic mechanisms in LON 954 tremorogenesis, a reduction in cyclic AMP levels may be an important factor in the observed effects.

The effect of propranolol phentolamine and pimozide on drug-induced anorexia in the mouse.

Pimozide was a potent antagonist of (+)amphetamine, diethylpropion, mazindol and phentermine anorexia in the mouse. Phentolamine and propranolol produced no such antagonism, but either potentiated or had no effect on the drug-induced anorexia. Although the mechanism of action of the four anorectic agents appears to involve dopamine receptor agonist activity, an antagonist or partial agonist effect at noradrenergic receptors may also be involved.

Modification of the 5-hydroxytryptophan-induced head-twitch response by exogenous endocrine agents.

Estrogens both alone and in combination with progestagens, gonadotrophins, gonadotrophin-releasing factor, corticosteroids, and corticotrophin antagonise the head-twitch response produced by 5-hydroxytryptophan in mice. In contrast, a potentiation was seen following thyroid hormones, thyrotrophin, and thyrotrophin-releasing hormone. Pre-treatment with androgens had no significant effect. Possible mechanisms for these interactions are discussed.

Some observations on the anorectic activity of prostaglandin F2alpha.

1 Intracerebroventricular injection of prostanglandin F2alpha (10-40 microgram) decreases food intake in a dose-dependent manner in rats trained to consume their daily total food intake in a 2 h period. 2 This anorexia is also observed in satiated rats, which had ad libitum access to food. 3 The anorectic activity of prostaglandin F2alpha is not modified by changes in the internal environment of the body after food intake, such as increased blood glucose and insulin levels and decreased fatty acid levels, or by the presence or absence of food in the stomach, as is evident from the anorectic activity of prostaglandin F2alpha in partially satiated rats. 4 The anorexia is not due to pain or irritative properties of prostaglandin F2alpha since induction of comparable pain with 3% acetic acid does not affect food intake in rats deprived of food for 22 hours. 5 Anorectic doses of prostaglandin F2alpha when injected intraperitoneally cause hypothermia. 6 The results suggest that the inhibitory activity of prostaglandin F2alpha on food intake is at both peripheral and central sites. 7 Prostaglandin F2alpha-induced anorexia is associated with the behavioural tranquilization that is seen after the ingestion of food.

Anorectic activity of prostaglandin precursors.

1 Intraperitoneal and intragastric (i.g.) administration of prostaglandin precursors arachidonic (2 mg, 15 mg/kg, i.p; 30 mg/kg i.g.), linolenic (100 mg/kg i.p.; 200 mg/kg, i.g.) and linoleic (15, 100 mg/kg, i.p.; 100 mg/kg, i.g.) acids to 22 h food-deprived rats inhibits food intake. 2 This anorexia is similar to that induced by prostaglandin F2alpha (1 mg/kg, i.p.). 3 At anorectic doses these fatty acids do not cause pyrexia, in fact arachidonic acid causes hypothermia. 4 Prior treatment with indomethacin (15 mg/kg) and paracetamol (50 mg/kg) specifically reverses the anorexia and the behavioural satiety induced by the three fatty acids, while not affecting prostaglandin F2alpha-induced suppression of food intake. 5 Results of the present experiments suggest that both physiological and pharmacological modification of appetite could be brought about through an effect on prostaglandin generating systems.

The production of an alternative laboratory model of the Parkinson syndrome using a new benzylimidoylurea derivative LON 954.

N-carbamoyl-2-(2,6-dichlorophenyl) acetamidine hydrochloride (LON 954) causes a reproducible rest tremor in mice, of rapid onset and short duration with no associated rigidity or akinesia and in the absence of any marked changes in body temperature or accompanying peripheral parasympathomimetic effects. This tremor can be antagonised by the dopamine receptor agonists L-Dopa, bromocriptine, nomifensine and piribedil, as well as by anticholinergic anti-Parkinson drugs having an inhibitory effect on dopamine uptake such as benapryzine and benztropine. In contrast, benzhexol, orphenadrine and amantadine had no effect. LON 954 appears to be more specific than oxotremorine for the detection of drugs having therapeutic potential in the treatment of Parkinson's disease, particularly those exerting their effect through dopaminergic systems. An antagonist (BS 100-141), which is a structural isomer of LON 954, is also described.

Estrogen potentiating activity of two spiro compounds having approximately similar molecular dimensions to stilbestrol.

Pharmacological investigation of members of a series of synthetic spiro derivatives with similar molecular dimensions to stilbestrol revealed that two compounds, spiro[cyclohexane-1,2'-tetralin]-1,4'-dione and spiro[cyclohexane-1,2'-indan]-1,4'-diol, exhibited a marked ability to potentiate stilbestrol at doses which had no intrinsic estrogenic activity. It is postulated that such compounds may be of use in reducing the side effects associated with estrogen therapy.

The pharmacology of N-carbamoyl-2-(2,6-dichlorophenyl)acetamidine hydrochloride (LON-954) a new tremorogenic agent.

The tremorogenic properties of a series of benzylimidoylurea derivatives are described. The most potent member, N-carbamoyl-2-(2,6-dichlorophenyl) acetamidine hydrochloride (LON-954), produces a reproducible, dose-dependent rest tremor in the mouse with oral doses of 5-100 mg/kg which is also seen in other species (rat, cat, dog, rabbit). The tremor is of constant frequency, rapid onset and short duration. It is not accompanied by akinesia, muscle ridigity, antinociceptive activity, parasympathomimetic effects or marked hypothermia and in these respects differs from tremor produced by oxotremorine. Pretreatment with a microsomal enzyme inhibitor had no effect on the tremor. An LD50 of 165 mg/kg p.o. was calculated in the mouse. After repeated administration both acute and chronic tolerance developed to the tremorogenic effects of LON-954. Evidence for a central site of action is presented, since the tremor could be reproduced following injection of small quantities (50-100 microgram) into the cerebral ventricles of the mouse. Furthermore, the use of spinal, decorticate and and decerebrate rats indicated that although tremor is not of cortical origin, it arises in an area rostral to the inferior colliculi. The mechanism underlying the tremor appears to involve dopaminergic pathways, since the action of LON-954 was antagonised by L-dopa and apomorphine and potentiated by pimozide. Atropine and carbachol were without effect. It is suggested that LON-954 could be used as an alternative to oxotremorine for the detection of anti-Parkinson drugs, particularly those exerting their effects through dopaminergic mechanisms.

Modification of oxotremorine tremor and hypothermia by injections of drugs into the cerebral ventricles of the mouse.

1. The effect of various agents injected into the cerebral ventricles of the mouse, upon the tremor and hypothermia produced by oxotremorine (0.5 mg/kg i.p.) was studied. 2. Acetylcholine (0.1-10 mug) produced a dose-dependent potentiation of oxotremorine tremor in contrast to the multiphasic effect it had on the accompanying hypothermia. Both tremor and hypothermia were antagonised by very small doses (0.1-10 ng) of atropine. 3. Dopamine and apomorphine (0.1-10 mug) had no significant effect on oxotremorine tremor. A dose-dependent potentiation of hypothermia was, however, observed. 4. Noradrenaline (0.1-10 mug), phentolamine and propranolol (0.1-10 mug) produced no significant effect on tremor and inconsistent results were obtained on hypothermia. 5. Neither tremor nor hypothermia were affected by 5-hydroxytryptamine (1-20 mug). 6. Oxotremorine tremor appears to be due solely to the activation of cholinergic pathways, whereas the production of hypothermia is brought about via a system involving both cholinergic and dopaminergic components. 5-Hydroxytryptamine is not involved.