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K Svensson

Publications and source records attributed to K Svensson.

At least 127 records · Page 7Linked to original sources
PubMed1986

(+)-AJ 76 and (+)-UH 232: central stimulants acting as preferential dopamine autoreceptor antagonists.

The biochemical and behavioral effects of the putative dopamine autoreceptor antagonists cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin, (+)-AJ 76 and cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin, (+)-UH 232, were evaluated in various in vivo models in rats. Both compounds produced a marked elevation in brain dopamine synthesis and turnover with only slight effects on the synthesis and turnover of serotonin (5-HT) and noradrenaline being noted. (+)-AJ 76 and (+)-UH 232 also failed to antagonize the decrease in cortical noradrenaline synthesis rate caused by the alpha 2 agonist clonidine. The apomorphine-induced decrease in dopamine synthesis rate in gamma-butyrolactone (GBL) treated animals was completely blocked by (+)-AJ 76 and (+)-UH 232 but not by d-amphetamine or methylphenidate. In activity experiments using habituated animals, (+)-AJ 76 and (+)-UH 232 produced locomotor stimulation and weak stereotypies and antagonized the sedative effects of low doses of apomorphine. Locomotor hyperactivity induced by apomorphine or the dopamine agonist DiPr-5,6-ADTN was antagonized by (+)-UH 232 and to a lesser degree by (+)-AJ 76. The locomotor hyperactivity produced by (+)-AJ 76, (+)-UH 232 and methylphenidate was completely prevented by reserpine pretreatment and partially blocked by the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MT), whereas d-amphetamine-induced hyperactivity was only antagonized by alpha-MT pretreatment. It is concluded that (+)-AJ 76 and (+)-UH 232 produce behavioral stimulation via a preferential antagonism on central dopamine autoreceptors, an action different from that of all known stimulants including apomorphine, d-amphetamine and methylphenidate. (+)-AJ 76 and (+)-UH 232 possess but weak antagonistic effects on postsynaptic dopamine receptors and only the latter compound is able to induce sedation in rats.

4-Butyrolactone↗
PubMed1986

Central dopaminergic properties of HW-165 and its enantiomers; trans-octahydrobenzo(f)quinoline congeners of 3-PPP.

In the further development of CNS dopamine autoreceptor active compounds related to 3-PPP, the transfused 7-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline HW-165 and its enantiomers were synthesised. This paper describes the basic pharmacological properties of these latter, novel "atypical" dopaminergic agents, based on an extensive series of biochemical and behavioural experiments in rats. By and large, the pharmacological activities of HW-165 - essentially, if not exclusively, residing in its (4aS,10bS)-(-)-enantiomer - were similar to those displayed by (S)-(-)-3-PPP, indicating the simultaneous presence of central dopamine (autoreceptor) agonist and weak (postsynaptic) antagonist properties in the molecule. Thus, in non-pretreated animals HW-165 and its active species monotonically suppressed the spontaneous locomotion without causing catalepsy or other appreciable motor disabilities, and at the same time selectively reduced the dopamine synthesis, release/turnover and utilisation. Some differences in these biochemical responses to HW-165 [racemate or (-)-enantiomer] were, however, noted in the limbic vs. striatal brain areas (e.g. decrease of dopamine synthesis particularly in the limbic parts). On the other hand, while failing to reverse reserpine-induced akinesia or to elicit stereotyped behaviour, the agents markedly inhibited the dopamine synthesis in either of the dopamine-dominated cerebral regions in the reserpinised as well as in gamma-butyrolactone (GBL)-treated rats. As shown for racemic HW-165 after reserpine pretreatment, the inhibition of dopamine synthesis was completely and stereoselectively blocked by (+)-butaclamol, thereby supporting direct dopamine receptor interaction. Racemic HW-165 readily antagonised the d-amphetamine-induced locomotor hyperactivity. Apomorphine-induced hyperactivity was, however, distinctly more resistant to antagonism by HW-165 [racemate or (-)-enantiomer]. Moreover, the latter agents fully prevented the apomorphine-induced inhibition of striatal dopamine synthesis in otherwise non-pretreated rats, while only partly counteracting this effect of apomorphine in the limbic regions of such animals, and in either brain area of rats treated with gamma-butyro-lactone. The findings are interpreted within the context of the mixed dopamine agonist/antagonist properties (referred above) of HW-165 and its active (-)-species in relation to the adaptive state of central dopamine receptors and possible regional variations in feedback strength and organisation.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Butyrolactone↗
PubMed1986

(+)-UH 232 and (+)-UH 242: novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors.

The (+)- and (-)-enantiomers of the 2-aminotetralin derivatives cis-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232) and cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (UH 242), were pharmacologically evaluated in rats in an extensive series of in vivo biochemical and behavioral experiments. These studies showed that the (+)- and (-)-enantiomers have differential effects on central dopamine (DA) receptors. Thus, (-)-UH 242 is a DA-receptor agonist stimulating both pre- and postsynaptic receptors. (-)-UH 232 is also active as a DA receptor agonist, although with much lower potency than (-)-UH 242. In contrast, (+)-UH 242 and (+)-UH 232 are characterized as DA receptor antagonists. Both (+) forms markedly accelerated DA synthesis and turnover and reversed the biochemical and behavioral effects of apomorphine. Locomotor activity was stimulated by the (+)-enantiomers over a wide dose range; hypomotility was induced only by high doses. The pharmacological profile of the (+)-enantiomers clearly differs from that of classical neuroleptics and suggests a preferential antagonistic action on DA autoreceptors. (+)-UH 232 and (+)-UH 242 may prove useful as experimental tools and as potential therapeutic agents (selectively increasing DA-ergic neurotransmission), e.g. in geriatric practice.

4-Butyrolactone↗
PubMed1986

A homologous series of N-alkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins: central dopamine receptor antagonists showing profiles ranging from classical antagonism to selectivity for autoreceptors.

N-alkylated and N,N-dialkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins were tested for central dopamine receptor antagonism using in vivo biochemical and behavioral models in rats. The di-methyl analogue showed a profile similar to classical dopamine receptor antagonists. It produced a marked hypomotility including catalepsy and a pronounced increase in dopamine synthesis rate. This compound also displaced DiPr-5, 6-ADTN from striatal binding sites and antagonized the hyperactivity induced by the ligand. In contrast, the mono-propyl analogue increased locomotor activity and dopamine synthesis rate over a wide dose range. This compound failed to antagonize the hyperactivity induced by DiPr-5, 6-ADTN and to displace this in-vivo binding ligand. Thus, the mono-propyl analogue appears to lack postsynaptic dopamine receptor antagonistic properties; it seems to produce its effects via a selective dopamine autoreceptor antagonism. The di-ethyl and di-propyl, but not the dibutyl, analogues were also active in the models used. Whereas the di-ethyl compound shows a profile similar to classical dopamine receptor blockers, the di-propyl compound appears to act preferentially on autoreceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1986

Effects of capsaicin on central monoaminergic mechanisms in the rat.

The acute and chronic effects of capsaicin (s.c.) on the monoamines in the preoptic region + hypothalamus (RPO-H), spinal cord, substantia nigra and striatum were studied. Levels of DOPA, DA, DOPAC, HVA, 3-MT, NA, Trp, 5-HTP, 5-HT and 5-HIAA were determined by means of liquid chromatography (HPLC-EC). In response to acute capsaicin treatment, the levels of DA, DOPAC and DA synthesis rate (DOPA formation) were increased in a dose-dependent manner in the RPO-H and spinal cord. The disappearance rate of NA was accelerated in both regions. In substantia nigra, increased DOPAC levels were found whereas the levels of 3-MT were decreased in striatum after acute capsaicin treatment. Only minor changes on the levels of 5-HT and 5-HIAA in the regions studied were noted. Neonatal or adult capsaicin treatment failed to affect the levels of NA, DA and 5-HT (measured two months or five weeks after injection, respectively) in the regions studied. A capsaicin injection to rats pretreated with the drug as adults did not affect either the monoamines in the RPO-H and spinal cord or the body temperature. In contrast, in rats pretreated with capsaicin as neonates, a second injection of the drug to adult animals elicited hypothermia and changes in monoamines similar to those observed in naive animals.

Animals↗
PubMed1986

Enantiomers of 3-(3,4-dihydroxyphenyl)- and 3-(3-hydroxyphenyl)-N-n-propylpiperidine: central pre- and postsynaptic dopaminergic effects and pharmacokinetics.

This study emphasizes the importance of the metabolic conversion of the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) into their catechol analogues, the enantiomers of 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine. These isomers are both shown to be excellent substrates for COMT, with a slight preference for the S-(-) enantiomer. Assessment of the dopaminergic activity of these catechols and the results from the determination of brain levels of the enantiomers of 3-PPP and their metabolites indicate that the metabolites probably do not alter the pharmacological profiles established for (R)-(+)- and (S)-(-)-3-PPP. The conversion of the monophenols into catecholic metabolites is only 1-5%, and the further conversion of these catecholic metabolites into methoxylated analogues is very rapid. However, the very interesting observation was made that, when inhibiting COMT by means of tropolone and subsequently treating the rats with high doses of (S)-(-)-3-PPP (ip), postsynaptic dopaminergic activity was elicited. This has never been seen for (S)-(-)-3-PPP without tropolone pretreatment and might indicate that, in this special case, the catecholic metabolite affects the in vivo pharmacological profile of (S)-(-)-3-PPP.

Animals↗
PubMed1986

Covalent binding of reactive intermediates to hemoglobin in the mouse as an approach to studying the metabolic pathways of 1,2-dichloroethane.

CBA mice were given 14C-labelled 1,2-dichloroethane by intraperitoneal injection. Metabolic pathways leading to the formation of electrophilic intermediates were studied through the determination, by ion-exchange chromatography, of the products of reaction of this labelled substrate with nucleophilic sites in hemoglobin and DNA. The products found in hemoglobin and the pattern of alkylation suggest that chloroacetaldehyde and S-(2-chloroethyl)glutathione are important reactive metabolites in vivo. The alkyl purines, 7-(2-oxoethyl)guanine and 7-[S-(2-cysteine)-ethyl]guanine, were found in DNA hydrolysates, as well as in the urine.

Alkylation↗
PubMed1985

The putative dopamine autoreceptor agonist B-HT 920 decreases nigral dopamine cell firing rate and prolactin release in rat.

Recent behavioural and biochemical investigations have suggested that the alpha-2 receptor agonist B-HT 920 is also a centrally acting dopamine (DA) agonist with a selectivity for autoreceptors. It is presently demonstrated that B-HT 920, in contrast to the structurally related alpha-2 agonist B-HT 933, effectively reduces the firing rate of nigral DA neurons both after intravenous and microiontophoretic administration. Furthermore, B-HT 920, but not B-HT 933, decreases plasma levels of prolactin in reserpine pretreated rats. The electrophysiological as well as the neuroendocrine effects of the drug were antagonised by DA antagonists but not by alpha-2 receptor antagonists. The data support the contention that B-HT 920 acts as an agonist at central DA autoreceptors. Furthermore, they reinforce the hypothesis that lactotroph DA receptors are more similar to DA autoreceptors than to postsynaptic DA receptors in the brain.

Action Potentials↗
PubMed1985

Dopamine receptor-mediated hypothermia induced in rats by (+)-, but not by (-)-3-PPP.

The novel dopaminergic agents (+)- and (-)-3-PPP were evaluated for their effects upon thermoregulation in rats maintained at room temperature (approximately 22 degrees C). Although approximately 30 times less potent than apomorphine, (+)-3-PPP induced a clearcut, dose-dependent and haloperidol/pimozide-reversible hypothermia. In contrast, the (-)-enantiomer per se lacked a significant effect upon rat body temperature. However, (-)-3-PPP clearly attenuated apomorphine-induced hypothermia. Simultaneous biochemical investigations confirmed the presence of central dopamine (DA) agonist and antagonist properties for (+)- and (-)-3-PPP, respectively, at the doses employed. The results are compared to the agonist and antagonist effects of the 3-PPP enantiomers in various other central DA receptors systems. Particular reference is made to the recent hypothesis by Carlsson (J. Neural Transm. 57 (1983) 309, relating agonist intrinsic activity to the DA receptor responsiveness state, in turn determined by the endogenous tone. Based on the findings with (+)- and (-)-3-PPP it is suggested that DA receptors mediating hypothermia in the rat may be more akin to 'normosensitive' postsynaptic than to highly 'agonist-responsive' autoreceptors.

Animals↗
PubMed1985

Prediction of long-term outcome of tibial osteotomy in medial gonarthrosis.

To predict the long-term outcome after tibial osteotomy for medial gonarthrosis, multivariate statistical techniques were used and prognostic equations were defined. A comparison between different evaluation systems was also performed. Clinical and radiographic data from 81 patients followed up for more than 7 years were used. Twenty-eight preoperative variables were analysed in relation to the outcome at 7 years with the multivariate procedures discriminant analysis and cluster analysis. Among the variables, knee flexion and walking capacity were found to be the most dominant factors. Excluding the undercorrected osteotomies, preoperative walking capacity was now the dominating variable for prediction. Seven years postoperatively only small differences were found between the evaluation criteria of pain relief, London Hospital score, and HSS score. The discriminant functions for the highest ranked evaluation criteria are given in the text, as are dendrograms showing the patterns of interdependence between the evaluation criteria. Thus it was possible to transform clinical entities into factors suitable for determination and calculation of postoperative evaluation. The most commonly used evaluation systems had very similar discriminant functions showing good agreement.

Female↗
PubMed1985

Rat brain serotonin: biochemical and functional evidence for a sex difference.

Male and female rats were compared with respect to brain serotonin (5-HT) levels, synthetic capacity, receptor sensitivity, and CNS functions. Levels of whole brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were higher in females. The accumulation of 5-HT after treatment with the monoamine oxidase inhibitor pargyline alone and in combination with the 5-HT precursor L-tryptophan was greater in females than in males. 5-HT increased and 5-HIAA decreased to the same extent in both sexes after administration of the 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The temperature fall after all drug treatments was greater in females, but the "5-HT behavioural syndrome" was more pronounced in females merely after pargyline plus tryptophan; the behavioural response after 8-OH-DPAT did not differ between the sexes. These results are indicative of sex differences in the brain 5-HT neuronal systems. They are discussed in relation to differences between males and females in sexual behaviour, aggression and affective disorders.

Animals↗
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

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

Design, findings and five-year follow-up of preventive medical lipid intervention clinic in Malmö.

In a separate lipid intervention clinic integrated within the framework of a multiphasic preventive medical population program in Malmö, 401 of 2431 screening attenders in a male birth-year cohort born in 1927 and 1928 had elevated values of triglyceride and/or cholesterol. Hypertriglyceridemia was more than three times as frequent as hypercholesterolemia. Of these attenders 20% had normal values at the second control, 5% did not attend the second test and 92 (31.2%) of the remaining were referred to other clinics because of other high risk factors. Thus, 209 (8.6% of the screening attenders) males born in 1927 and 1928 attended the lipid clinic for isolated hyperlipidemia. Disregarding a 5-year drop-out frequency of 13 sections, a significant reduction in the lipids was obtained during the follow-up period in those remaining in treatment. This study demonstrates the feasibility in taking care of hyperlipidemic individuals after a screening detection program. Detection and treatment of hyperlipidemia should of course also be initiated in the individual case in ordinary medical practice.

Cholesterol↗