The effects of phenylpropanolamine and other sympathomimetics on food consumption and motor activity in mice

The effects of phenylpropanolamine on motor activity and on food intake were compared with those of S-amphetamine, ephedrine, 2-aminoindane and fenfluramine in groups of mice. Motor activity was additionally measured in mice pretreated with levodopa and benserazide, and food intake in mice pretreated with alpha-methyl-p-tyrosine. Amphetamine (2.5 mg kg-1) increased motor activity, phenylpropanolamine (10-40 mg kg-1) and 2-aminoindane (2.5-10 mg kg-1) decreased activity whilst ephedrine (2.5-40 mg kg-1) had a biphasic effect. Fenfluramine (10-40 mg kg-1) had negligible effect on activity. In mice pretreated with levodopa and benserazide both phenylpropanolamine and 2-aminoindane caused a massive increase in motor activity whilst fenfluramine's action was not affected in the same way. Whilst the anorectic action of fenfluramine was considerably potentiated in mice pretreated with alpha-methyl-p-tyrosine, that of amphetamine, ephedrine, 2-aminoindane and phenylpropanolamine was either unaffected or initially antagonized. It is concluded that the mechanisms of motor and anorectic actions of phenylpropanolamine are similar to those of amphetamine.     

The effects of stereoisomers of 2-amino-6(7)- and 9-amino-6-trifluoromethylbenzonorbornenes on food intake, brain serotonin concentration, and monoamine oxidase activity

To evaluate the importance of the conformation of fenfluramine in eliciting its various central nervous system effects, the isomers of 2-amino-6(7)- and 9-amino-6-trifluoromethylbenzonorbornene were employed as conformationally defined analogs of norfenfluramine. In this series of isomeric amines, the exo-2 and anti-9 isomers resemble the fully extended conformation of fenfluramine, whereas the endo-2 and syn-9 isomers resemble the folded conformation. The exo-2 and anti-9 isomers were equi-effective in reducing food intake in the rat, but were approximately seven times less potent than fenfluramine. The endo-2 and syn-9 isomers had no effect on food intake up to a dose of 40 mg/kg. All of the isomers were as effective as amphetamine in inhibiting brain monamine oxidase type B. These isomers also inhibited monoamine oxidase type A to the same extent as type B, but were significantly less potent than amphetamine in inhibiting this form of the enzyme. The effects at anorectic doses on brain serotonin (5-HT) concentration were also studied. Although fenfluramine decreased brain 5-HT concentration, the exo-2, syn-9 and anti-9 isomers had no significant effect. The endo-2 isomers caused an 11% decrease in 5-HT concentration, but this effect was observed at higher doses of the compound. The data suggest that the fully extended conformation of fenfluramine is preferred over the folded conformation for eliciting its anorectic activity. However, no conclusion can be made for the conformational requirements for the other biological responses investigated in this study.     

Aminoindanes--the next wave of 'legal highs'?

Due to its closed ring system, 2-aminoindane is a conformationally rigid analogue of amphetamine. Internet websites offering synthetic compounds as 'research chemicals' have recently been advertising 5,6-methylenedioxy-2-aminoindane (MDAI), 5, 6-methylenedioxy-N-methyl-2-aminoindane (MDMAI), 5-iodo-2-aminoindane (5-IAI), and 5-methoxy-6-methyl-2-aminoindane (MMAI). The chemistry, pharmacology, and toxicological aspects of this new class of psychoactive substances are reviewed, as these could become the next wave of 'legal highs'.     

Interaction of d-amphetamine with central nervous system depressants on food intake and spontaneous motor activity of mice

Pentobarbital, chlordiazepoxide, diazepam, meprobamate and piperacetazine antagonized the anorectic effect of d-amphetamine. However, their antagonism of the motor stimulant effect of d-amphetamine was not uniform. Pentobarbital significantly increased but diazepam and piperacetazine significantly decreased the motor stimulant effect of d-amphetamine. Chlordiazepoxide and meprobamate did not alter the amphetamine effect on motor activity.     

Dopaminergic effects of non-hydroxylated rigid analogs of apomorphine

A series of rigid analogs of apomorphine lacking aromatic hydroxyl substitutents were evaluated for dopaminergic properties. Three compounds, N-methyl-N-propyl-2-aminotetralin (Me-Pr-2-AT), N-N-dipropyl-2-aminotetralin (Di-pr-2-AT) and N,N-dipropyl-2-aminoindane (Di-Pr-2-AI) induced emesis in dogs, contralateral circling in unilaterally lesioned rats, and inhibited prolactin secretion. The induced circling responses, however, were attenuated by prior treatment with alpha-methyl-p-tyrosine methyl ester (AMPTME) and the compounds were weak inhibitors of 3-H-dopamine binding in calf caudate homogenates. The possibility that these agents may be metabolically activated in vivo is discussed.     

Effect of (-)-trans-PAT, a novel 5-HT2C receptor agonist, on intake of palatable food in mice

(1R,3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT) is a novel compound that has full-efficacy agonist activity at human 5-HT(2C) receptors and inverse agonist/antagonist activity at 5HT(2A) and 5HT(2B) receptors. In the present paper we describe its effects on food intake in non-deprived C57BL/6 mice adapted to eating a palatable dessert meal each day. PAT showed a dose-related inhibition of food intake with a 50% inhibitory dose of 4.2 mg/kg. The dose-effect curve was similar to that obtained using WAY-161503. Abnormal behaviors were not observed by casual inspection following administration of PAT. The anorectic effect of PAT was additive with that of amphetamine. When PAT, or PAT+amphetamine, were injected 2 h before access to food, most of the anorectic activity had dissipated, indicating that PAT has a biologically effective period of about 1 h. Four daily injections of PAT were associated with some, but not complete loss of the initial anorectic effect; this differs from the rapid tolerance that has been reported to fenfluramine anorexia and suggests that different mechanism(s) are involved in the loss of anorexia.     

In vitro actions of NN-dimethyl-2-aminoindane and related compounds

The actions of 2-aminoindane, 2-amino-1,2,3,4-tetrahydronaphthalene and amphetamine and their N-methyl and NN-dimethyl derivatives on the guinea-pig ileum were compared. All, except the tertiary 2-aminoindane, inhibited the responses to electrical stimulation and it is suggested that this is not fully explained by their sympathomimetic properties. NN-Diemthyl-2-aminoindane increased these responses and caused contractions of the unstimulated ileum due to a nicotine-like action. The indane series was more effective in producing contractions of the ileum than the other compounds. The three tertiary derivatives antagonized competitively the actions of histamine on the ileum and those of 5-hydroxy-tryptamine on the rat uterus.     

Acute tolerance to amphetamine in rats

Two groups of rats were given amphetamine intravenously at 5-min intervals (5 or 10 mg/kg/h) for 8h. Two control groups received saline infusions. On the second day a test dose of 10 mg/kg amphetamine was given to all groups. Body temperature, food intake, and motor behavior were registered every 30 or 60 min. The results showed the development of acute tolerance to the hyperthermic effect within 3–5 h. Tolerance was still visible on the 2nd day. There was also tolerance to the anorectic effect, which was evident on the 2nd day. One element of stereotyped behavior (swaying) also decreased during the amphetamine infusions.     

Comparative study of the anorexigenic activity of 5-(3,4-dichlorophenoxymethyl)-2-amino-2-oxazoline HCl and d-amphetamine in different species

Like amphetamine, the oxazoline caused significant anorexia in mice, rats, cats and dogs. It did not cause nausea or emesis in cats or in dogs. Upon chronic administration, it caused significant reduction of body weight of rats without any signs of apparent toxicity. In approximately equipotent anorectic doses, its stimulant effects on both the central nervous and the cardiovascular systems were less than those of d-amphetamine. The anorectic activity of oxazoline was approximately the same in aurothio-glucose-obese and nonobese mice. This fact may suggest that, like amphetamine, the compound was acting on the feeding centers in the lateral hypothalamic area.     

The effect of selective lesioning of brain catecholamine-containing neurons on the activity of various anorectics in thr rat.

An intraventricular injection of 6-hydroxydopamine to rats pretreated with pargyline, a procedure which produces a marked decrease of brain catecholamines without significant changes in the serotonin levels, significantly antagonizes the anorectic effect of amphetamine, phentermine, mazindol and diethylpropion, while the reduction of food intake induced by other drugs such as fenfluramine, p-chloroamphetamine, SE 780 and SKF 1-39728 is not significantly affected. The data suggest an involvement of brain catecholamines in the anorectic effect of amphetamine, phentermine, mazindol and diethylpropion whereas other mechanisms appear to be involved in the activity of the other anorectics studied.     

In vitro actions of NN-dimethyl-2-aminoindane and related compounds

The actions of 2-aminoindane, 2-amino-1,2,3,4-tetrahydronaphthalene and amphetamine and their N-methyl and NN-dimethyl derivatives on the guinea-pig ileum were compared. All, except the tertiary 2-aminoindane, inhibited the responses to electrical stimulation and it is suggested that this is not fully explained by their sympathomimetic properties. NN- Dimethyl-2-aminoindane increased these responses and caused contractions of the unstimulated ileum due to a nicotine-like action. The indane series was more effective in producing contractions of the ileum than the other compounds. The three tertiary derivatives antagonized competitively the actions of histamine on the ileum and those of 5-hydroxytryptamine on the rat uterus.     

Structure-activity studies on amphetamine analogs using drug discrimination methodology

Animals (rats) trained to discriminate 1.0 mg/kg of S(+)-amphetamine sulfate from saline, using a standard operant training procedure, were administered doses of various amphetamine analogs in tests of stimulus generalization in order to study structure-activity relationships (SAR). The types of structural variation of the amphetamine molecule that were investigated included (a) benz-fusion of the aromatic nucleus, (b) alpha-demethylation of the alkyl side chain, (c) conversion of the benzylic methylene to a carbonyl group, and (d) conformational restriction of the side chain. Benz-fusion and alpha-demethylation appear to have a detrimental effect on activity in that none of these analogs produced amphetamine-appropriate responding. However, the carbonylated analog, i.e., cathinone, was found to be equipotent with amphetamine. Furthermore, as with amphetamine, the S-isomer of cathinone was found to be more active than its enantiomer. With respect to the conformationally-restricted analogs, the most potent compound was 2-aminotetralin which was about half as active as racemic amphetamine.     

钩藤碱对苯丙胺依赖大鼠伏核和杏仁核中NR2B蛋白表达的影响

目的:研究钩藤碱对苯丙胺依赖大鼠伏核和杏仁核中NR2B蛋白表达的影响。方法:采用条件性位置偏爱实验和免疫组化技术。结果:(1)建立了苯丙胺(2mg.kg-1,连续4d)诱导的位置偏爱模型,氯胺酮及钩藤碱低、中、高剂量均可消除苯丙胺诱导的位置偏爱效应,随钩藤碱剂量增加其效应加强,且本身无精神依赖性;(2)苯丙胺模型组大鼠伏核和杏仁核NR2B蛋白表达增加,氯胺酮及钩藤碱中、高剂量抑制NR2B表达,低剂量及本身对NR2B表达无影响。结论:伏核和杏仁核NR2B蛋白表达参与了钩藤碱抗苯丙胺依赖作用的分子机制。     

Anorexigenic effects of d-amphetamine and 1-dopa in the rat

The effect of amphetamine and 1-dopa was compared in 22-hr food- and water-deprived rats. Amphetamine produced marked anorexia, and 1-dopa significantly reduced food intake at 200 mg/kg. Following pretreatment with RO 4-4602, a decarboxylase inhibitor, 100 mg/kg of 1-dopa, a dose that did not significantly affect eating, produced marked anorexia. The anorectic effect of both amphetamine and 1-dopa was antagonized by propranolol, a β adrenergic antagonist. Phentolamine, an a-adrenergic antagonist, potentiated the anorectic effect of amphetamine and 1-dopa. Haloperidol (0.1 mg/kg), a dopamine antagonist, failed to prevent the anorexia due to amphetamine but accentuated that due to 1-dopa. Methysergide, a serotonin antagonist, also failed to prevent the anorexigenic effect of amphetamine. Finally, the administration of 1-dopa with or without peripheral decarboxylase inhibition resulted in more than twice the increase in hypothalamic dopamine levels without significant changes in 5-HT or norepinephrine levels. The data show that the anorexigenic effect of amphetamine and 1-dopa are similar and indicate a functional role for both norepinephrine and dopamine neurons in feeding behaviour in the rat.     

Animal Studies

The effect of amphetamine on spontaneous motor behavior has been studied in satiated and in food deprived rats. Amphetamine (1 mg/kg) evoked a large increase in motor activity in satiated animals, and an even larger increase in motor activity in deprived animals. The magnitude of motor stimulation by amphetamine in deprived animals was roughly proportional to the duration of deprivation. Food deprivation by itself did not increase motor activity. Neither sympathectomy nor adrenalectomy modified the response to amphetamine or to amphetamine plus deprivation. The data suggest that food deprivation potentiates the action of amphetamine by a central rather than a peripheral mechanism.     

The effect of viloxazine on drug-induced inhibition of food intake in the rat

In male Wistar rats trained to eat their normal daily dietary requirement in a restricted 2 h period, dose-dependent decreases in food consumption were produced by fenfluramine, tiflorex, mazindol and amphetamine. The antidepressant drug viloxazine (Vivalan) alone did not alter food intake significantly, nor did the drug prevent the inhibitory effects of either mazindol or amphetamine. However, complete prevention of the inhibitory effect of fenfluramine was achieved with 7.5 mg kg-1 viloxazine, while 40 mg kg-1 viloxazine similarly prevented the anorectic action of tiflorex. An interaction involving 5-hydroxytryptaminergic mechanisms is suggested, and since viloxazine given after fenfluramine or tiflorex produced no reversal of the inhibition of food intake, it is suggested that viloxazine prevents access of the anorectic agents to their site of action. The clinical significance of these interactions is discussed.     

Study on the metabolism of 5,6-methylenedioxy-2-aminoindane (MDAI) in rats: identification of urinary metabolites

1.?5,6-Methylenedioxy-2-aminoindane (MDAI) is a member of aminoindane drug family with serotoninergic effect, which appeared on illicit drug market as a substitute for banned stimulating and entactogenic drugs.

2.?Metabolism of MDAI, which has been hitherto unexplored, was studied in rats dosed with a subcutaneous dose of 20?mg MDAI.HCl/kg body weight. The urine of rats was collected within 24?h after dosing for analyses by HPLC-ESI-HRMS and GC/MS.

3.?The main metabolic pathways proceeding in parallel were found to be oxidative demethylenation followed by O-methylation and N-acetylation. These pathways gave rise to five metabolites, namely, 5,6-dihydroxy-2-aminoindane, 5-hydroxy-6-methoxy-2-aminoindane, N-acetyl-5,6-methylenedioxy-2-aminoindane, N-acetyl-5,6-dihydroxy-2-aminoindane and N-acetyl-5-hydroxy-6-methoxy-2-aminoindane, which were found predominantly in the form of corresponding glucuronides and sulphates. However, the main portion of administered MDAI was excreted unchanged.

4.?Minor metabolites formed primarily by hydroxylation at various sites include cis- and trans-1-hydroxy-5,6-methylenedioxy-2-aminoindane, 5,6-methylenedioxyindan-2-ol and 4-hydroxy-5,6-methylenedioxy-2-aminoindane.

5.?Identification of all metabolites except for glucuronides, sulphates and tentatively identified 4-hydroxy-5,6-methylenedioxy-2-aminoindane was supported by synthesised reference standards.     

Effects of indorenate on food intake: a comparison with fenfluramine and amphetamine

Indorenate (TR3369, 5-methoxytryptamine b-methylcarboxylate HCl) is a 5-HT₁-like receptor agonist with hypotensive activity. Here, we describe that indorenate also decreases food intake (ED₅₀ 26.1 mg/kg) without an appreciable effect in water intake (the estimated ED₅₀ for water was 589.8 mg/kg). The anorectic activity of indorenate was compared to the effects of amphetamine and other serotonin agonists; the effect of indorenate was smaller than those of the other compounds; however, the effect of indorenate was specific to food, whereas all the other drugs also produced significant decrements in water intake. The serotonin antagonists cinanserin, cyproheptadine, methergoline and methysergide effectively prevented the decrease in food intake produced by indorenate and fenfluramine. Haloperidol, a dopaminergic antagonist, was ineffective in preventing the effect of indorenate although it prevented the anorectic effect of amphetamine. The present results suggest the participation of serotoninergic, but not dopaminergic mechanisms, in the decrease in food intake produced by indorenate.     

The effect of viloxazine on drug-induced inhibition of food intake in the rat

In male Wistar rats trained to eat their normal daily dietary requirement in a restricted 2 h period, dose-dependent decreases in food consumption were produced by fenfluramine, tiflorex, mazindol and amphetamine. The antidepressant drug viloxazine (Vivalan) alone did not alter food intake significantly, nor did the drug prevent the inhibitory effects of either mazindol or amphetamine. However, complete prevention of the inhibitory effect of fenfluramine was achieved with 7·5 mg kg^?1 viloxazine, while 40 mg kg^?1 viloxazine similarly prevented the anorectic action of tiflorex. An interaction involving 5-hydroxytryptaminergic mechanisms is suggested, and since viloxazine given after fenfluramine or tiflorex produced no reversal of the inhibition of food intake, it is suggested that viloxazine prevents access of the anorectic agents to their site of action. The clinical significance of these interactions is discussed.     

Anorectic effect of lisuride and other ergot derivatives in the rat

Three ergot derivatives, lisuride, lergotrile and bromocriptine, given to rats trained to eat 4 h a day, induced a dose- and time-related anorexia. They were more potent in this context than either amphetamine or fenfluramine. Lisuride and lergotrile failed to increase locomotor activity or to induce stereotyped behaviour at doses corresponding to the ID50 on food intake. At this dose, bromocriptine slightly stimulated motor activity. The anorectic effect of the three compounds was selectively antagonized by blockers of dopamine (DA) receptors in the central nervous system but not by either inhibiton of catecholamine synthesis or blockade of alpha- or beta-adrenoceptors or of serotonergic receptors. Also two blockers of 'peripheral' DA receptors failed to antagonize ergoline-induced anorexia. These findings indicate that stimulation of DA receptors involved in feeding behaviour was responsible for the anorexigenic effect of the ergot derivatives investigated. In most instances this effect occurred at dose levels which failed to induce central stimulant effects.