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H Wikström

Publications and source records attributed to H Wikström.

At least 73 records · Page 4Linked to original sources
PubMed1988

NSD 1034: an amino acid decarboxylase inhibitor with a stimulatory action on dopamine synthesis not mediated by classical dopamine receptors.

The accumulation rates of 3,4'-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after inhibition of aromatic amino acid decarboxylase (AADC) by 3-hydroxybenzylhydrazine (NSD 1015) or 1-(DL-seryl)-2- (2,3,4-trihydroxybenzyl)hydrazine (Ro 4-4602) have widely been used as measurements of the in vivo synthesis rates of monoamines. However, the values of dopamine (DA) turnover in rat striatum obtained using these drugs are much lower than values obtained by other methods. This discrepancy prompted us to further investigate the AADC inhibitor 1-(3-hydroxybenzyl)-1-methylhydrazine (NSD 1034) which earlier has been shown to give a DOPA accumulation rate in the striatum of the same magnitude as other measures of DA turnover. NSD 1034 was found to give a more than twofold higher DOPA accumulation rate than NSD 1015, NSD 1024, NSD 1039, NSD 1055 and Ro 4-4602 in the striatum. Also, in the limbic region and the hemispheres, but not in the substantia nigra, the DOPA accumulation was higher after NSD 1034 than after NSD 1015, but the difference was less pronounced. There was, however, no difference in 5-HTP accumulation between the drugs in any of the brain parts investigated. Although the DOPA accumulation rates are higher after NSD 1034 than after NSD 1015, the NSD 1015-induced DOPA accumulation seems to be more sensitive to changes in dopamine receptor occupancy. The different DOPA accumulation rates obtained with NSD 1015 and NSD 1034 are not due to differences in MAO inhibition, to interference with classical DA receptors, or to different degrees of AADC inhibition, but to an ability of NSD 1034 to stimulate DA synthesis. In addition, under certain conditions NSD 1034 also has a DA releasing action, like amphetamine. It is proposed that NSD 1034 and amphetamine stimulate DA synthesis and release by a common mechanism. The low value of DA synthesis rate, obtained when measured as DOPA accumulation after NSD 1015, is due to a substantial efflux of DOPA from the brain. The efflux of DOPA is equally large after NSD 1034 but the loss is compensated for by an increase in DOPA synthesis.

5-Hydroxytryptophan↗
PubMed1988

Occurrence and pharmacological significance of metabolic ortho-hydroxylation of 5- and 8-hydroxy-2-(di-n-propylamino)tetralin.

Aromatic ortho-hydroxylation in the liver might be one of several possible reasons for the low bioavailabilities of the potent, centrally acting dopaminergic and serotoninergic agonists 5- and 8-hydroxy-2-(di-n-propylamino)tetralin, respectively. In vitro and in vivo experiments showed that such an oxidative metabolism did indeed take place. However, the amount of hydroxylated metabolites found in the brain was estimated to represent only 0.3% of the total amount of drug administered. The O-methylation rates of these catechols were also measured in vitro and showed that 5,6-dihydroxy-2-(di-n-propylamino)tetralin is a poor substrate for catechol O-methyltransferase (COMT) and that its 7,8-dihydroxy isomer is virtually devoid of substrate activity. No O-methylated metabolites were detected in the in vivo samples analyzed. A new synthetic strategy was applied to achieve the isomeric catechols studied. 5-Methoxy- or 8-methoxy-2-(di-n-propylamino)tetralin was lithiated in the ortho position and the metalated species was subsequently quenched in nitrobenzene, yielding the methoxy hydroxy isomers, which were heated in 48% aqueous HBr to achieve the corresponding catechols.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Conformational analysis of 2-aminoindans and 2-(aminomethyl)indans in relation to their central dopaminergic effects and a dynamic dopamine receptor concept.

Conformational analyses on differently substituted 2-aminoindans of significant pharmacological interest were carried out by the molecular mechanics method (MM2). An X-ray structure of (R)-4-methoxy-2-aminoindan has shown the ammonium nitrogen [-)-D-tartaric acid salt) in an axial position. From comparison with other, highly potent, centrally acting dopamine (DA) receptor agonists, it can be predicted that the active enantiomer (R)-4-hydroxy-2-(di-n-propylamino)indan should have its nitrogen atom in an equatorial position. This places it close to the aromatic ring plane, which is one of several prerequisites for potent DA receptor agonism. MM2 correctly calculates (R)-4-methoxy-2-aminoindan and (R)-4-hydroxy-2-(dialkylamino)indan to be more stable in the N-axial and N-equatorial conformations, respectively. Conformational analysis of the dimethyl model compound of the moderately potent dopaminergic phenylpropylamine analogue 4-hydroxy-2-[(di-n-propylamino)methyl]indan was also carried out, in order to see if any conformations of this compound satisfy the requirements for dopaminergic agonism. Two such stable conformations were found.

Brain↗
PubMed1987

Resolved cis-10-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline : central serotonin stimulating properties.

cis-10-Hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b -octahydrobenzo[f]quinoline (4) is a centrally acting serotonin (5-HT) receptor agonist of moderate potency. Due to its semirigid character and the obvious similarity between (4aR,10bS)-4 and more potent, centrally acting 5-HT receptor agonist cis-(1S,2R)-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (2), we carried out the preparation (via resolution of 6, a precursor of 4) and the pharmacological testing of the enantiomers of 4. We were able to show that the active enantiomers of 4 and 2 coincide in terms of stereochemistry, i.e., that it is the 4aR,10bS enantiomer of 4 that is the more active one. The absolute configuration was assigned on the basis of single-crystal X-ray analysis of the precursor (+)-6 of the active enantiomer (-)-4. Conformational analysis with molecular mechanics (MM2) calculations were performed on the N-methyl analogues of compounds cis-(1S,2R)-2 (cis-(1S,2R)-3) and cis-(4aR,10bS)-4 (cis-(4aR,10bS)-7). Both ammonium and free amine forms were subjected to these calculations. The results show a preference for the N-equatorial conformation, which is corroborated by the X-ray structure of (+)-6.HCl. The relatively low potency of compound cis-(4aR,10bS)-4 might be explained by unfavorable direction of the N-lone pair (or ammonium hydrogen) bond in this compound as compared to cis-(1S,2R)-2 and trans-(4aR,10bR)-5, which can be predicted to be the more active enantiomer of compound 5.

Animals↗
PubMed1987

The dopaminergic moiety of the ergots: a controversial topic studied with molecular mechanics.

Conformational analyses of the side chain of model compounds of the in vivo active dopamine receptor agonist 4-[2-(di-n-propylamino)ethyl]indole (DPAI) were performed with molecular mechanics calculations. The results from these calculations, together with the possibility of meta hydroxylation of indoles in vivo, led to the proposal of fitting 6-hydroxy-4-[2-(di-n-propylamino)ethyl]indole (6-OH-DPAI), (S)-5-hydroxy-N,N-dialkyl-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-ylami nes and (S)-5-hydroxy-2-(dialkylamino)tetralins in a common concept, considering both stereochemistry and hydrogen-bond function in such an overlap. This study emphasizes the importance of considering both conformational analysis and the possibilities of metabolic activation when performing structure-activity studies based on flexible compounds and in vivo data. The answer to the question as to which part of the ergot molecule is responsible for its dopaminergic effect is thus ambiguous. It is possible that the pyrrolylethylamine moiety of the ergots contributes to both in vitro and in vivo effects, and that their 13-OH metabolites contribute, possibly significantly, to their in vivo effects.

Chemical Phenomena↗
PubMed1987

(+)-cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin: a potent and highly stereoselective 5-hydroxytryptamine receptor agonist.

C1-Methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1) were synthesized and tested for central 5-HT and dopamine receptor activity by use of a biochemical test method in rats. cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin (8) was found to be a 5-HT receptor agonist. The (+)-enantiomer of 8 had a potency equal to that of 1, whereas (-)-8 and the trans isomer (+/-)-9 were inactive.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

N-substituted 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines and 3-phenylpiperidines: effects on central dopamine and sigma receptors.

N-Substituted analogues of trans-7- and trans-9-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (trans-7- and trans-9-OH-OHBQ) were tested for dopamine (DA) D2 receptor affinity by using in vitro [3H]spiperone and in vivo 5,6-di-n-Pr-ADTN binding assays. Potencies at central pre- (auto-) and postsynaptic DA receptors were determined by a biochemical and a behavioral method, respectively. Corresponding data were included for analogous, resolved 3-(3-hydroxyphenyl)piperidines and a few other substituted, racemic 3-phenylpiperidines. Beside the central dopaminergic effects of these compounds, previously reported sigma receptor affinity data [[3H]-(+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine; [3H]-(+)-3-PPP] were also taken into account for a comparison of the structure-activity/affinity relationships of these compounds at these two receptor types. Larger N-substituents in both phenylpiperidines and OHBQs increase both pre- and postsynaptic dopaminergic activity. An n-propyl group gives high dopaminergic efficacy at both receptor sites (pre- and postsynaptic) in all series. However, even higher dopaminergic potency is observed for trans-7-OH-OHBQs and (S)-3-(3-hydroxyphenyl)piperidines with N-substituents larger than n-propyl. In contrast, trans-4-n-Bu-9-OH-OHBQ is inactive, and (R)-3-(3-hydroxyphenyl)-N-n-butylpiperidine is less active at central DA receptors than its corresponding n-propyl analogue. This implies interesting differences in N-substituent sensitivity for the different classes of compounds with respect to the direction of their respective N-substituents at the drug-receptor interaction. The stereochemical and steric demands for sigma receptor affinity are much less stringent. The general trend is that, up to a certain size, the more lipophilic the N-substituent, the higher the affinity for sigma receptor sites.

Animals↗
PubMed1987

Quantitative structure-activity relationships and eudismic analyses of the presynaptic dopaminergic activity and dopamine D2 and sigma receptor affinities of 3-(3-hydroxyphenyl)piperidines and octahydrobenzo[f]quinolines.

Data from the preceding paper were examined by QSAR and eudismic analyses. A fair parabolic relationship was found between the lipophilicity (measured by a RP-HPLC method) and the sigma-receptor affinity of 3-(3-hydroxyphenyl)piperidines (3HPP derivatives) and octahydrobenzo[f]quinolines (OHBQ derivatives). As far as the dopamine D2 receptor is concerned, the trans-7-hydroxy-OHBQ derivatives show a 10-fold higher affinity than the eutomeric S enantiomers of 3HPP derivatives, once lipophilicity has been accounted for. This difference in affinity is suggested to correspond to the energy necessary for the 3HPP derivatives to adopt the receptor-bound conformation. The R enantiomers of 3HPP derivatives display no apparent increase in D2 affinity with increasing lipophilicity, and indeed the eudismic index in this series increases with affinity (eudismic affinity quotient = 0.70), in agreement with a recent model of the binding of N-propyl-3HPP (3PPP) enantiomers to the D2 receptor. The selectivity in sigma/D2 affinities was found to depend on both lipophilicity and configuration of the ligands; thus, the selectivity is maximal for log kw values of ca. 1.7-2.1 and is much larger for the R than for the S enantiomers of 3HPP derivatives.

Phenanthrenes↗
PubMed1987

Structural determinants of sigma receptor affinity.

The structural determinants of sigma receptor affinity have been evaluated by examining a wide range of compounds related to opioids, neuroleptics, and phenylpiperidine dopaminergic structures for affinity at sigma receptor-binding sites labeled with (+)-[3H]3-PPP. Among opioid compounds, requirements for sigma receptor affinity differ strikingly from the determinants of affinity for conventional opiate receptors. Sigma sites display reverse stereoselectivity to classical opiate receptors. Multi-ringed opiate-related compounds such as morphine and naloxone have negligible affinity for sigma sites, with the highest sigma receptor affinity apparent for benzomorphans which lack the C ring of opioids. Highest affinity among opioids and other compounds occurs with more lipophilic N-substituents. This feature is particularly striking among the 3-PPP derivatives as well as the opioids. The butyrophenone haloperidol is the most potent drug at sigma receptors we have detected. Among the series of butyrophenones, receptor affinity is primarily associated with the 4-phenylpiperidine moiety. Conformational calculations for various compounds indicate a fairly wide range of tolerance for distances between the aromatic ring and the amine nitrogen, which may account for the potency at sigma receptors of structures of considerable diversity. Among the wide range of structures that bind to sigma receptor-binding sites, the common pharmacophore associated with high receptor affinity is a phenylpiperidine with a lipophilic N-substituent.

Animals↗
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

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

A molecular mechanics approach to the understanding of presynaptic selectivity for centrally acting dopamine receptor agonists of the phenylpiperidine series.

Molecular mechanics (MMP2) calculated geometries and conformational energies have been employed in an attempt to elucidate the molecular basis for presynaptic dopamine receptor selectivity of centrally acting agonists of the phenylpiperidine series. A receptor interaction model based on the McDermed receptor concept, on superimpositions of calculated structures, and on conformational analysis is presented. The model focuses on the interaction between N-alkyl substituents and the receptor. From comparisons with rigid structures having either agonistic or antagonistic properties it is concluded that the presynaptically selective compound (S)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S)-3PPP) is acting as an agonist in one rotameric form and as an antagonist in another one. The selectivity of (S)-3PPP and the nonselectivity of its enantiomer are suggested to be due to differences in the interactions between N-alkyl substituents and the receptor. The receptor model presented led to the hypothesis that the piperidine ring in the compounds studied should be equivalent to a N-methyl group in its receptor interactions. Examples are given in support of this idea. Presynaptic selectivity was predicted for an aminotetralin derivative and was also observed in subsequent testing.

Brain↗
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

In-vitro and in-vivo metabolism of the presynaptic dopamine agonist 3-PPP to a catecholic analogue in rats.

The dopamine agonist 3-PPP and its enantiomers are hydroxylated in-vitro by rat liver microsomes to the catecholamine 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine (4-OH-3-PPP) with Km and Vmax values of about 1 microM and 2 nmol (mg protein)-1 min-1 respectively. As the catecholamine formed appears to be a good substrate for catechol-O-methyltransferase, in-vivo catecholamine formation in rats from 3-PPP was only detectable after inhibition of COMT by tropolone. The resulting brain levels of 4-OH-3-PPP, as measured by HPLC with electrochemical detection 45 min after administration, were about 350 pmol g-1 after i.p., and about 100 pmol g-1 after s.c. injection of 45 mumol kg-1 3-PPP, with no significant difference between racemic, ( + ) or (-) 3-PPP. It was estimated that these catecholamine levels represent about 1-5% of the 3-PPP levels after i.p., and about 0.2-0.5% after s.c. administration of 3-PPP. The relevance of this metabolic conversion of 3-PPP for its pharmacological profile is discussed.

Animals↗