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H Wikström

Publications and source records attributed to H Wikström.

87 records · Page 5Linked to original sources
PubMed1984

Production of nerve growth-stimulating factor(s) from chick embryo heart cells. Use of Cytodex 3 microcarriers and serum-free media.

Medium conditioned by embryonic chick heart cells is known to support extensive neurite outgrowth from autonomic and sensory neurons. In the present report we describe the use of microcarrier cell culture with serum-free media to scale up the production of the nerve growth-stimulating factors. A growth medium composed of DME /F10 supplemented with insulin, transferrin, human serum albumin and fibronectin in combination with a low molecular weight (MW) fraction of fetal calf serum (FCS) or a mixture of FGF, dexamethasone, calmodulin and thrombin supported the heart cell proliferation at a rate similar to that of medium with 10% FCS. Furthermore, the level of successively accumulated nerve growth activity measured in a bioassay with sympathetic ganglia proved to be nearly equivalent to what was obtained when cells were grown in medium containing serum. The results confirm the potential of microcarrier cell culture in serum-free media for the production and subsequent recovery of a specific cell product.

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

Dopamine receptors involved in prolactin secretion pharmacologically characterized by means of 3-PPP enantiomers.

3-(3-Hydroxyphenyl)-N-n-propylpiperidine (3-PPP) is a novel compound existing in two enantiomers which, as judged by recent biochemical and behavioural studies, both have clearcut though differential effects on central dopamine (DA) receptors. Thus, while both enantiomers act in low doses as agonists preferentially on autoreceptors, in higher doses the (+)-form is an agonist also postsynaptically while the (-)-form acts as an antagonist on postsynaptic DA receptors in the striatum and in the limbic system. In the present study both enantiomers were evaluated with respect to their effects on pituitary DA receptors involved in prolactin release. In previously untreated rats, no increase in prolactin release was observed after administration of either enantiomer in low or high doses. The lack of effect of high doses of the (-)-form indicates that DA receptors on the lactotrophs are pharmacologically different from postsynaptic DA receptors in nigrostriatal and mesolimbic systems. The finding that both enantiomers exerted a dose-dependent prolactin suppressive effect in reserpine-pretreated animals suggests instead that DA receptors on the lactotrophs are pharmacologically similar to DA autoreceptors in the brain. The effect of both 3-PPP enantiomers on prolactin release in reserpine-pretreated animals was antagonized by haloperidol, sulpiride and metoclopramide while pimozide and clozapine appeared less active. This finding is discussed with respect to possible selectivity on pre- vs. postsynaptic DA receptors for various antagonists.

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

Antidyskinetic action of 3-PPP, a selective dopaminergic autoreceptor agonist, in Cebus monkeys with persistent neuroleptic-induced dyskinesias.

Four Cebus apella monkeys with persistent dyskinetic movements induced by earlier long-term administration of haloperidol were subjected to a trial of the dyskinesia-modifying effects of a novel dopamine autoreceptor agonist 3-PPP (3[3-hydroxyphenyl]-N-n-propyl-piperidine). Three monkeys had choreic dyskinesia involving trunk and extremities whereas one had a buccolingual form including tongue protrusion with choreoathetotic twitching and twisting movements of the tongue. Two monkeys (1 choreic, 1 buccolingual) responded with dose-dependent symptom alleviation to 3-PPP, 1-4 mg/kg, with no signs of concomitant sedation or catalepsy. In the monkey with buccolingual dyskinesia all dyskinetic signs disappeared completely 2 hours after 2 mg/kg of 3-PPP. This animal participated in a separate study where the same doses of 3-PPP but also its enantiomers were given. The (-) enantiomer was a more potent antidyskinetic agent than the (+) enantiomer, the racemate falling between these two. Four mg/kg of the (+) enantiomer precipitated an amphetamine-like excitation and after 4 hours aggravation of dyskinesia was noted. These observations support the notion that the (+) enantiomer has both postsynaptic and presynaptic stimulatory effects, whereas the (-) enantiomer acts as a presynaptic dopamine receptor agonist.

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↗
PubMed1982

Monophenolic octahydrobenzo[f]quinolines: central dopamine- and serotonin-receptor stimulating activity.

Eight monophenolic cis- and trans-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines have been synthesized and tested for central dopamine- and serotonin-receptor stimulating activity, using biochemical and behavioral tests in rats. The trans-7-, -8-, and -9-hydroxy isomers all elicited central pre- and postsynaptic dopaminergic receptor stimulation, while the trans-10-hydroxy isomer was devoid of dopaminergic activity but instead showed central serotoninergic activity. In all four isomeric pairs, the trans isomers were consistently much more potent than their corresponding cis analogues. The apparent presynaptic selectivity of the dopaminergic cis isomer cis-9-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline could not be confirmed due to the toxic properties of this compound. Central dopamine receptors (autoreceptors and postsynaptic receptors) can accept dopaminergic compounds with one of possibly two N-substituents being larger than n-propyl, if this substituent is properly oriented in relation to the rest of the molecule.

5-Hydroxytryptophan↗
PubMed1981

Effects of a new type of 5-HT receptor agonist on male rat sexual behavior.

8-Methoxy-2-(di-n-propylamino) tetralin (8-OMe-DPAT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) are two new drugs exerting selective actions on brain 5-HT neurotransmission. In the present experiments we have investigated the effects of these two drugs on male rat sexual behavior. It was found that both drugs reduce the number of intromissions preceding ejaculation and shorten the ejaculation latency. These effects are extremely pronounced and several animals ejaculate at the first intromission. In addition 8-OH-DPAT produced a slight reduction of the post-ejaculatory interval. There were no significant effects on latency to initiate copulation or in the number of mounts preceding ejaculation. Finally, sexual behavior was partly or completely restored in castrated male rats after injection with 8-OMe-DPAT or 8-OH-DPAT.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1981

Monophenolic 2-(dipropylamino)indans and related compounds: central dopamine-receptor stimulating activity.

Monophenolic (2-(dipropylamino)indans and related compounds have been synthesized and tested for central dopamine-receptor stimulating activity, using biochemical and behavioral tests in rats and emesis tests in dogs. The active compounds possess similar relative potencies in eliciting the three different dopamine-receptor mediated effects measured. 4-Hydroxy-2-(dipropylamino)indan was the most potent of the new compounds. The corresponding 5-hydroxy analogue was less active. 4-Hydroxy-2-[(dipropylamino)methyl]indan is a new type of dopaminergic agent with a phenylpropylamine moiety in its framework instead of the phenylethylamine structure, common to most dopamine-receptor agonists. This compound was 10-20 times less active than apomorphine. 6,7,8,9-Tetrahydro-1-hydroxy-N,N-dipropyl-5H-6-benzocycloheptenylamine and 5-hydroxy-2-[(dipropylamino)methyl]tetralin were both inactive. Since the intramolecular distances between functional groups in the indans studied here are different from those in, for example, apomorphine, it is concluded that a certain variation of these distances can be accepted by the receptor. It could also be demonstrated that the position of the OH group on the aromatic ring is of importance for the activity and that emetic activity may be associated with dopaminergic agonists of the indan as well as of the tetralin type of structure.

Animals↗
PubMed1981

3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity.

Thirty compounds related to the selective dopamine-autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine have been synthesized and tested for central dopamine-autoreceptor stimulating activity. The 3-(3-hydroxyphenyl)piperidine moiety seems indispensable for high potency and selectivity. Introduction of an additional hydroxyl group into the 4 position of the aromatic ring gives a compound with dopaminergic activity but lacking selectivity for autoreceptors. 3-(3-Hydroxyphenyl)-N-n-propylpyrrolidine, 3-(3-hydroxy)-N-n-propylperhydroazepine, and 3-(3-hydroxyphenyl)quinuclidine were all inactive. The most potent compounds were the N-isopropyl-, N-n-butyl-, N-n-pentyl-, and N-phenethyl-substituted 3-(3-hydroxyphenyl)piperidine derivatives. None of the compounds investigated seemed to have central noradrenaline- or serotonin-receptor stimulating activity.

5-Hydroxytryptophan↗
PubMed1979

N-Alkylated 2-aminotetralins: central dopamine-receptor stimulating activity.

In order to define the structural requirements of N-substituents of 2-aminotetralins as central dopamine receptor agonists, a series of N-alkyl- and N,N-dialkyl-substituted 2-amino-5-hydroxy- and 2-amino-5-methoxytetralins have been synthesized and evaluated. The compounds were tested biochemically and behaviorally for dopaminergic activity. From the biochemical data it is concluded that an n-propyl group on the nitrogen is optimal for activity. The corresponding N-ethyl-substituted compounds are slightly less active, while the absence of N-ethyl or N-propyl groups give almost inactive compounds. It could be demonstrated that this is due to steric and not to lipophilic factors. It is suggested that a possible requirement for a potent agonist is that one of it N substituents must fit into a receptor cavity which, because of its size, can maximally accommodate an n-propyl but also smaller groups like ethyl or methyl. The active compounds appeared to give a similar relative pre- and postsynaptic stimulation and had also similar activities for the limbic system and for striatum. None of the compounds listed seemed to have central noradrenaline- or serotonin-receptor stimulating activity.

5-Hydroxytryptophan↗
PubMed1978

Pivaloyl esters of N,N-dialkylated dopamine congeners. Central dopamine-receptor stimulating activity.

In order to test for dopamine-receptor stimulating activity a new, sensitive biochemical screening method was designed. For behavioral studies and for determination of the duration of action on the compounds, motor activity measurements were used. O,O'-Dipivaloyl-N,N-dipropyldopamine (4) was the only derivative of a series of dipivaloyl-N,N-dialkyldopamines studied that showed any significant activity. However, the monopivaloyl ester 2-(3-pivaloyloxyphenyl)-N,N-dipropylethylamine (8) seemed to be more potent. The same relationship was found for the corresponding phenols, N,N-dipropyldopamine (3) and 2-(3-hydroxyphenyl)-N,N-dipropylethylamine (7), although both were more active than their pivaloyl esters.

Administration, Oral↗