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Biomedical subjects

S Hjorth

Publications and source records attributed to S Hjorth.

At least 109 records · Page 6Linked to original sources
PubMed1985

Sub-chronic administration of (-)-3-PPP and central dopamine receptor sensitivity changes.

The effects of sub-chronic treatment with (-)-3-PPP (8 mg/kg, s.c., b.i.d. for 21 days), a dopaminergic agent with mixed agonist/antagonist properties, were investigated by means of behavioural and in vivo biochemical methods. There was no change in basal locomotor activity and central dopamine (DA) synthesis after 24 hours withdrawal. A slight, though significant reduction of the locomotor suppressive effect and of the DA synthesis-stimulating effect of acute (-)-3-PPP challenge doses of 0.125 and 1.0 mg/kg (s.c.), respectively, were demonstrated in (-)-3-PPP-pretreated as compared to vehicle-pretreated rats. No change in either action was evident after acute challenge with 8.0 mg/kg (s.c.) of the drug. The plasma levels of (-)-3-PPP were virtually unchanged by pretreatment with active drug. The findings are discussed in terms of a modest down- and up-regulation of DA autoreceptors and postsynaptic receptors, respectively, induced by the subchronic (-)-3-PPP treatment.

Animals↗
PubMed1985

Dopamine-receptor agonists: mechanisms underlying autoreceptor selectivity. I. Review of the evidence.

The behavioural, biochemical, neuroendocrinological and electrophysiological actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, are extensively reviewed. (+)-3-PPP acts in a fashion similar to classical direct-acting DA agonists, stimulating both DA autoreceptors and postsynaptic DA receptors, although in some situations the drug appears to exhibit partial agonist activity. (-)-3-PPP exerts a variety of actions in different pharmacological models. Either agonistic, antagonistic or both agonistic and antagonistic activity are observed depending on the anatomical location of the relevant DA receptors and the experimental conditions. The actions of transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline (HW 165) are also discussed. These agents possess a similar spectrum of action to (-)-3-PPP suggesting a new generation of DA agonists which exhibit variable intrinsic activity at different DA receptors. Finally, evidence is presented indicating that the 3-PPP enantiomers display selectivity for DA receptors.

Acetylcholine↗
PubMed1985

(-)-Pindolol stereospecifically inhibits rat brain serotonin (5-HT) synthesis.

(-)-Pindolol (4 mg/kg, i.p.) stereospecifically and selectively inhibited rat brain 5-HT synthesis. The DA and NA synthesis remained unaffected by pindolol (either enantiomer) treatment, and the (-)-pindolol-induced decrease in 5-HT synthesis was not prevented by reserpine pretreatment. The results indicate that, in addition to its beta-adrenergic properties, (-)-pindolol may act as an agonist at synthesis-controlling 5-HT receptors (autoreceptors ?) in the rat CNS.

Adrenergic beta-Antagonists↗
PubMed1985

Novel dopamine receptor agonists and antagonists with preferential action on autoreceptors.

The enantiomers of cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin and its methyl ether have been synthesized. The compounds were tested for central dopamine (DA) receptor activity, by using biochemical and behavioral tests in rats. The (1R,2S)-(-) enantiomers of 1 and 2 are characterized as centrally acting DA-receptor agonists while the corresponding (1S,2R)-(+) enantiomers are characterized as centrally acting DA-receptor antagonists. Compounds (+)-1 and (+)-2 differ from classical neuroleptics in being able to increase DA synthesis rate in a wide dose range without reducing locomotor activity, suggesting a pronounced selectivity for DA autoreceptors. Also the (-) enantiomers seem to act preferentially on DA autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

Resolved monophenolic 2-aminotetralins and 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines: structural and stereochemical considerations for centrally acting pre- and postsynaptic dopamine-receptor agonists.

A detailed structure-activity relationship is revealed for resolved, centrally acting dopamine (DA) agonists acting on both pre- and postsynaptic DA receptors. The compounds resolved are 5- and 7-hydroxy-2-(di-n-propylamino)tetralin and cis- and trans-7-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinoline. By the superimposition of the structures of the more active enantiomers of these compounds with those of known dopaminergic agonists, apomorphine and ergolines, a new DA-receptor model is proposed as an outgrowth of current DA-receptor theories. One of the most important concepts of this receptor model is its emphasis on the possible positions taken by the N-substituents of dopaminergic compounds. One of these positions i sterically well defined while the other direction is sterically less critical. The model has been used to explain the lack of dopaminergic activity of some previously reported structures and also to predict properties of novel structures, including inherent chirality, which should be active at DA receptors. Hopefully, this heuristic DA-receptor model will lead to the discovery of more selective and potent pharmacological tools, which ultimately might lead to the development of therapeutic agents for treating diseases of dopaminergic function in the central nervous system.

Animals↗
PubMed1985

Cardiovascular effects in the Sprague-Dawley rat of 8-hydroxy-2(di-N-propylamino) tetralin, a selective 5-hydroxytryptamine receptor agonist.

The intravenous administration of 8-hydroxy-2(di-N-propylamino) tetralin, a selective 5-HT receptor agonist, caused a biphasic blood pressure response and bradycardia in Sprague-Dawley rats. The initial pressor response involved peripheral alpha 1-adrenoceptors since it was present in pithed rats and was antagonized by prazosin. Though the intracerebroventricular route of administration was not more effective the hypotension and bradycardia were probably of central origin. The bradycardia was prevented by pretreatment with atropine and propranolol suggesting an involvement of vagal as well as sympathetic activity. These results support the view that central 5-HT receptor activation reduces the blood pressure and heart rate.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1984

(+)- and (-)-3-PPP exhibit different intrinsic activity at striatal dopamine autoreceptors controlling dopamine synthesis.

Both enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP; 0.5-32 mg/kg s.c.) dose dependently reduced the increase in striatal dopamine (DA) synthesis rate produced by gamma-butyrolactone (GBL). Whereas (+)-3-PPP completely prevented the action of GBL, (-)-3-PPP was only partially effective. In addition, (-)-3-PPP partially antagonised the inhibitory action of apomorphine on the GBL-induced increase in DA synthesis rate. These findings suggest that (+)- and (-)-3-PPP act as full and partial agonists respectively, at striatal DA autoreceptors controlling DA synthesis.

4-Butyrolactone↗
PubMed1984

Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT).

The putative 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) produced in rats an increase in the number of shocks accepted in a modified Vogel's conflict test design. Subchronic pretreatment with p-chlorophenylalanine (PCPA) similarly caused release of the punished behavior. This anticonflict effect of PCPA was antagonized by both 5-hydrotryptophan and 8-OH-DPAT. Thus in naive animals 8-OH-DPAT exerting anticonflict effects acted like a 5-HT antagonist, whereas in subchronically PCPA-pretreated animals with presumably supersensitive 5-HT receptors, 8-OH-DPAT decreasing the number of accepted shocks acted like a 5-HT agonist.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1984

Differential effects of the enantiomers of 3-PPP on dopamine D1-receptors of isolated rabbit retina.

The effects of (+)- and (-)-3-PPP on cAMP levels of rabbit retina were investigated in vitro in the absence or presence of exogenous dopamine. In some experiments, a pre-incubation with reserpine was undertaken to deplete endogenous dopamine before the test. (+)- and (-)-3-PPP were found to be a weak dopamine-agonist and a weak dopamine-antagonist, respectively. Thus, the 3-PPP enantiomers may have opposite actions at the level of postsynaptic dopamine receptors, as previously suggested by studies in vivo.

Animals↗
PubMed1984

Central monoaminergic effects of two aporphine analogues to the putative serotonin-receptor agonist, 8-hydroxy-2-di-n-propylaminotetralin.

Two aporphine analogues to the potent and selective serotonin (5-HT) agonist, 8-hydroxy-2-di-n-propylaminotetralin (8-OH-DPAT) were studied with regard to their actions upon central monoaminergic systems. The biochemical and behavioural findings indicate that 8-hydroxy-N-methyl-aporphine (8-OH aporphine) and its N-n-propyl analogue (8-OH PNA) possess weak dopamine/noradrenaline antagonist- and agonist-like properties, respectively. In addition, both aporphines seemed to only weakly influence serotoninergic transmission. The latter findings are compared to those of known serotonin agonists (e.g. 8-OH-DPAT), and are discussed with particular reference to the structural requirements for activation of central 5-HT receptors.

Animals↗
PubMed1984

8-Hydroxy-2-(alkylamino)tetralins and related compounds as central 5-hydroxytryptamine receptor agonists.

A series of 2-(alkylamino)tetralins related to 8-hydroxy-2-(di-n-propylamino)tetralin (21) were prepared and tested as dopamine (DA) and 5-hydroxytryptamine (5-HT) receptor agonists. Several of the compounds were potent 5-HT agonists devoid of DA-mimetic effects. N-Ethyl or N-propyl substitution of 8-hydroxy-2-aminotetralin gave the most potent agonists. It was shown that the most potent compound, (+)-21, has the 2R configuration. 5,8-Di-methoxy-2-(di-n-propylamino)tetralin (31) was found to be a weak DA agonist devoid of 5-HT activity. The corresponding indan derivative, 4,7-dimethoxy-2-(di-n-propylamino)indan (39), has been reported to be active on both DA and 5-HT receptors. The 5-HT-stimulating properties of compounds 21 and 39 as compared to the incapability of compound 31 to activate the 5-HT receptor is tentatively explained by the assumed mode of binding of the compounds to the 5-HT receptor.

Animals↗
PubMed1984

C1-Methylated 5-hydroxy-2-(dipropylamino)tetralins: central dopamine-receptor stimulating activity.

C1-Methylated derivatives of the potent dopaminergic agonist 5-hydroxy-2-(di-n-propylamino)tetralin (6) have been synthesized and tested for central dopamine (DA) receptor stimulating activity, by using biochemical and behavioral tests in rats. Both cis- and trans-5-hydroxy-1-methyl-2-(di-n-propylamino) tetralin (4 and 3) may be classified as central DA-receptor agonists, albeit of lower potency than 6. The results obtained indicate that both 4 and 3 display DA-autoreceptor stimulation capacity. However, only one of the isomers, trans-3, is able to elicit clear-cut postsynaptic DA receptor agonist actions at larger doses. 5-Hydroxy-1,1-dimethyl-2-(n-propylamino) tetralin (5) was found to be inactive.

Animals↗
PubMed1984

Resolved 3-(3-hydroxyphenyl)-N-n-propylpiperidine and its analogues: central dopamine receptor activity.

Seven enantiomeric pairs of N-alkyl analogues of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP, 12) have been synthesized and evaluated pharmacologically (biochemistry and behavior) in order to examine their ability to interact with central dopamine (DA) receptors, particularly DA autoreceptors. In the R series it seems as if all compounds behave as classical DA receptor agonists with affinity and intrinsic activity for both pre- and postsynaptic receptors. The same bifunctional profile seems to be valid for the S enantiomers with N-substituents larger or bulkier than n-propyl. Likewise, the S enantiomers with ethyl or n-propyl N-substituents seem to have affinity for both pre- and postsynaptic receptors. In the total series, (S)-(-)-3-PPP [(S)-12] seems to be the most interesting compound both from the theoretical and the therapeutical point of view, possibly attenuating DA function in two different ways by stimulating the presynaptic receptors and blocking the postsynaptic receptors. This compound has been selected for extended pharmacological studies as a potential antipsychotic drug.

Animals↗
PubMed1983

Central dopamine receptor agonist and antagonist actions of the enantiomers of 3-PPP.

The two enantiomers of the putative centrally acting dopamine (DA) autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP (Hjorth et al. 1981), were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments unexpectedly revealed that both (+)- and (-)-3-PPP showed clear, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In contrast, although (-)-3-PPP similarly activates DA autoreceptors it acts concomitantly as an antagonist at postsynaptic DA receptors. Moreover, both behavioural and biochemical data on motor activity and DA synthesis and turnover suggest a preferential limbic action for the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with anatomical differences in the feedback organisation in central (viz, limbic vs striatal) DA systems. It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy.

Animals↗
PubMed1983

The effect of the enantiomers of 3-PPP on conditioned avoidance responding in the rat.

The effects of the enantiomers of 3-PPP on the maintenance of conditioned avoidance responding (CAR) were studied. The weak classical dopamine (DA) agonist (+)-3-PPP failed to interfere with CAR at any dose tested (0.8-13.6 mg/kg). Low doses of the drug produced sedation, while high doses produced behavioural stimulation. (-)-3-PPP, which acts as an antagonist on postsynaptic and as an agonist on autoreceptor DA sites, reduced avoidance with no effect on escape behaviour (6.8-13.6 mg/kg). However, this reduction of CAR occurred at doses much higher than those previously demonstrated to inhibit locomotor activity. This profile is discussed in relation to the behavioural effects of classical postsynaptic DA receptor antagonists.

Animals↗
PubMed1983

On the mode of action of 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, and its enantiomers. With particular reference to dopaminergic mechanisms in the central nervous system.

As part of an ongoing research project aimed at developing novel selective monoamine-, in particular DA-, receptor active agents the DA analogue 3-PPP, and its enantiomers, were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments revealed clearcut DA autoreceptor-stimulatory properties for all three compounds. In addition, the (+)-enantiomer displayed agonist and the (-)-enantiomer antagonist actions, respectively, on postsynaptic DA receptors. Thus the racemate was rendered a biological profile consonant with selective DA autoreceptor stimulation. Both biochemical and behavioural indices of central DA activity suggested a preferentially limbic impact for racemic 3-PPP and, more interestingly, the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with neuroanatomical differences in the feedback organisation in central (viz. limbic vs. striatal) DA systems. Due to their aforementioned characteristics, it is suggested that compounds like racemic and (-)-3-PPP may find potential clinical utility in the treatment of neuropsychiatric disorders, whilst lacking in the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy. An overview of the literature covering various in vivo and in vitro aspects of 3-PPP pharmacology is also included and taken into consideration, where pertinent. The results suggest that the use of chemical tools like 3-PPP and its enantiomers may provide new insight into central dopaminergic function, e.g. in investigating the consequences of interacting with specific DA receptor populations and the relative importance of pre- vs. postsynaptic feedback regulation in different DA systems, as well as their possible implications.

Animals↗
PubMed1983

The search for selective dopaminergic autoreceptor agonists.

In the course of a search for new selective dopamine (DA) autoreceptor agonists the DA analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, was resolved into its dextro-(+) and levo-(-) rotatory enantiomers. The compounds were pharmacologically evaluated by means of behavioural and biochemical methods. Surprisingly, both (+)-and (-)-3-PPP show clearcut, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA receptor agonist with activity on autoreceptors as well as postsynaptic receptors, whereas (-)-3-PPP similarly activates DA autoreceptors but, in contrast, concomitantly acts as an antagonist on postsynaptic DA receptors. Moreover, the behavioural/biochemical profile seems to indicate a preferential limbic action for the (-)-enantiomer. Such an action could be explained on the basis of different feedback arrangements in the nigrostriatal and mesolimbic DA systems and it is suggested that compounds such as (-)-3-PPP may find future clinical application as "second-generation" antipsychotic agents, lacking in the debilitating motor side effects produced by drugs in current therapeutic use.

Animals↗