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Biomedical subjects

U Hacksell

Publications and source records attributed to U Hacksell.

At least 91 records · Page 5Linked to original sources
PubMed1988

Structural factors of importance for 5-hydroxytryptaminergic activity. Conformational preferences and electrostatic potentials of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and some related agents.

The conformational characteristics of two series of 5-hydroxytryptamine (5-HT) receptor agonists, monophenolic N,N-dialkylated 2-aminotetralins and trans-2-phenylcyclopropylamines, have been studied by a combination of experimental (NMR spectroscopy) and theoretical (molecular mechanics and MNDO calculations) methods. In addition, molecular electrostatic potentials have been calculated for selected conformations and the absolute configuration of the potent 5-HT-receptor agonist (+)-cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin has been determined, by X-ray crystallography of the synthetic precursor, to be 1S,2R. Results obtained are discussed in terms of conformational, steric, and electronic requirements for 5-HT-receptor activation. It is suggested that different conformations of the 5-HT-receptor agonists (1R,2S)-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine [(1R,2S)-4] and its 3-hydroxy isomer (1R,2S)-5 are able to activate 5-HT receptors. The strongly increased stereoselectivity of 2, 4, and 5 as compared to that of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1) is rationalized on the basis of steric factors. Conformational factors appear to be responsible for the inability of the trans-C1-methyl-substituted derivative of 1 to activate 5-HT receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Derivatives of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide.

A series of tertiary and quaternary analogues (acyclic imides, sulfonimides, N-acetyl sulfonamides, and trifluoroacetamides) of the selective partial muscarinic agonist N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM 5,35) was synthesized. The compounds were found to be muscarinic agonists, partial agonists, or antagonists in the isolated guinea pig ileum. Replacement of the acetyl group or the N-methyl group of 35 and its analogues by a methanesulfonyl group abolished efficacy and decreased affinity at ileal muscarinic receptors. Trifluoroacetamide analogues of 35 also had lower affinity and efficacy than 35. Substitution of an acetyl group for the N-methyl group in compounds related to 35 decreased efficacy, but had no appreciable effect on affinity. Most of the tertiary amines showed central antimuscarinic activity as they antagonized oxotremorine-induced tremors in mice.

Acetamides↗
PubMed1988

Central dopaminergic and 5-hydroxytryptaminergic effects of C3-methylated derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin.

A number of stereochemically well defined C3-methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been synthesized, and their stereochemical characteristics have been studies by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations. The compounds were tested for activity at central 5-HT and dopamine (DA) receptors, by use of biochemical and behavioral tests in rats. In addition, the ability of the cis- and trans-8-hydroxy-3-methyl-2-(di-n-propylamino)tetralins (15 and 11) to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The stereoselectivity of the interaction of 11 and 15 with 5-HT receptors was much greater than that of 8-OH-DPAT. Observed rank order of potencies in the 5-HT1A binding assay corresponds to that in the in vivo biochemical assay.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Contact allergy to dehydroabietic acid derivatives isolated from Portuguese colophony.

7-oxodehydroabietic acid and 15-hydroxydehydroabietic acid were isolated as their methyl esters from Portuguese colophony of the gum rosin type and identified as contact allergens. Another oxidation product of dehydroabietic acid, 15-hydroxy-7-oxodehydroabietic acid, was synthesized and identified as a component of Portuguese gum rosin. 7-oxodehydroabietic acid was found to a be a grade III allergen according to the GPMT method. Guinea pigs induced with gum rosin showed only a low response to the isolated compounds, while patients with a known allergy to gum rosin reacted to a greater extent. The results imply that the content of oxidized dehydroabietic acids in gum rosin is too low to give a marked sensitization in the animals. However, the patients might have come in contact with the allergens in technically modified rosins. The compounds showed a pattern of cross-reactivity in the animal experiments as well as among the patch tested patients.

Abietanes↗
PubMed1988

Identification of 15-hydroperoxyabietic acid as a contact allergen in Portuguese colophony.

15-Hydroperoxyabietic acid (15-HPA) has been isolated from Portuguese colophony of the gum rosin type and identified as its methyl ester. The structure of the compound was elucidated using UV, IR, NMR and mass spectrometry. 15-HPA methyl ester was found to be an elicitor when tested in colophony-sensitized guinea-pigs. The sensitizing capacity was verified in the same species and 15-HPA methyl ester was considered to be a strong allergen. The eliciting potential was also verified in patients with known allergy to colophony. The Portuguese gum rosin investigated contained approximately 1% of 15-HPA. Based on its allergenicity and the amounts isolated, we conclude that 15-HPA is a main contact allergen in Portuguese gum rosin.

Abietanes↗
PubMed1987

Effects of the C3-methylated derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on central 5-hydroxytryptamine receptors.

The effects of the four possible C3-methylated stereoisomers of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) ((-)-CM-11, (+)-CM-11, (-)-CM-12, (+)-CM-12) on brain 5-hydroxytryptamine (5-HT) receptor functions were studied in rats. (-)-CM-11 and (+)-CM-12 inhibited dose dependently in all brain parts the accumulation of 5-hydroxytryptophan following decarboxylase inhibition. Their antipodes were inactive. The disappearance of 5-HT induced by alpha-propyldopacetamide was retarded by (-)-CM-11 and (+)-CM-12. The biochemically active isomers produced a flat body posture and forepaw treading. The results indicate that (-)-CM-11 and (+)-CM-12 stimulate 5-HT receptors directly although not as potently as 8-OH-DPAT. The concentration of dopamine was lowered and that of homovanillic acid was elevated by (+)-CM-11 and by both enantiomers of CM-12 in the corpus striatum and in the limbic system of rats. The accumulation of DOPA following decarboxylase inhibition was not markedly changed by any of the compounds. Locomotor activity was enhanced by (+)-CM-11 but not by any of the other compounds, and the effect was haloperidol-resistant. (+)-CM-11 induced no asymmetry in rats in which the corpus striatum was inactivated on one side. Thus, none of the isomers of CM-11 or CM-12 appears to have any effect on the dopamine receptors.

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

Resolved cis- and trans-2-amino-5-methoxy-1-methyltetralins: central dopamine receptor agonists and antagonists.

A series of 35 stereochemically well-defined C1-methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) have been synthesized. The compounds were tested for central DA receptor agonistic and antagonistic activity, by use of biochemical and behavioral tests in rats. In addition, the compounds were tested for in vivo interactions with 5,6-dihydroxy-2-(di-n-propylamino)tetralin (DiPr-5,6-ADTN). On the basis of pharmacological activity profiles, the active compounds have been classified into four groups: classical pre- and postsynaptic DA receptor agonists, DA receptor agonists with preferential action at presynaptic receptors, pre- and postsynaptic DA receptor antagonists, and DA receptor antagonists with preferential action at presynaptic receptors. Results obtained indicate that both 2R and 2S enantiomers of C5-oxygenated 2-aminotetralins may be able to bind to DA receptors but that only 2S antipodes are able to activate the receptors. O-Methylation of the C5-oxygenated (1S,2R)-2-amino-1-methyltetralin derivatives tends to increase their DA receptor antagonistic activity, whereas decrease of the size of the N-substituent(s) from n-propyl to ethyl or methyl appears to increase their activity at postsynaptic DA receptors.

Animals↗
PubMed1987

C3-methylated 5-hydroxy-2-(dipropylamino)tetralins: conformational and steric parameters of importance for central dopamine receptor activation.

C3-Methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) have been synthesized and their conformational preferences have been studied by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations (MMP2). The compounds were tested for activity at central DA receptors, by use of biochemical and behavioral tests in rats. (2R,3S)-5-Hydroxy-3-methyl-2-(di-n-propylamino)tetralin [(-)-8] was demonstrated to be a highly potent DA receptor agonist, while the other new compounds were of low potency or inactive. Results obtained confirmed the hypothesis that the tetralin inversion angle phi and the direction of the N-electron pair (N-H) tau N are conformational parameters of critical importance for DA D2 receptor activation in the 2-aminotetralin series. The high potency of (-)-8 allowed an extension of a previously defined "partial DA D2 receptor excluded volume".

Animals↗
PubMed1987

C1- and C3-methyl-substituted derivatives of 7-hydroxy-2-(di-n-propylamino)tetralin: activities at central dopamine receptors.

C1- and C3-methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) have been synthesized, and their conformational preferences have been studied by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics (MMP2) calculations. The compounds were tested for activity at central DA receptors, by use of biochemical and behavioral tests in rats. (1S,2R)-7-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin [(+)-10] was demonstrated to be sevenfold less potent than (2R)-7-OH-DPAT as a DA receptor agonist. The other new compounds were of lower potency or inactive.

Animals↗
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↗
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

Conformational analysis of the dopamine-receptor agonist 5-hydroxy-2-(dipropylamino)tetralin and its C(2)-methyl-substituted derivative.

The conformational preferences of the dopamine (DA) receptor agonist 5-hydroxy-2-(di-n-propylamino)tetralin (1) and the DA-inactive 5-hydroxy-2-methyl-2-(di-n-propylamino)tetralin (2) have been studied by use of molecular mechanics (MMP2) calculations and NMR spectroscopy. A good agreement is demonstrated between the experimentally determined (by NMR) and the calculated (by MMP2) conformational distribution of 1 and 2. In addition, there is a good agreement between bond distances and bond angles in the X-ray structure of the hydrobromide of 1 and those in the corresponding MMP2 conformation. Results obtained demonstrate that the energetically preferred conformations of 1 and 2 are different: Compound 1 preferentially adopts half-chair conformations with a pseudoequatorial nitrogen substituent whereas the low-energy conformations of compound 2 have a pseudoaxial nitrogen substituent. However, the results also indicate that the difference in conformational preferences is too small to account for the dopaminergic inactivity of 2. Therefore it is suggested that the steric bulk of the C(2)-methyl group per se prevents a proper alignment of (2S)-2 with DA receptors.

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

Dopaminergic 2-aminotetralins: affinities for dopamine D2-receptors, molecular structures, and conformational preferences.

A combination of X-ray crystallography, NMR spectroscopy, and molecular mechanics (MMP2) calculations was used to determine the three-dimensional structures and conformational preferences of the enantiomers of 5-hydroxy-2-(di-n-propylamino)tetralin and their C1-methylated derivatives. In addition, the affinities of the compounds for striatal 3H-spiroperidol- and 3H-N-n-propylnorapomorphine-binding sites were determined. In the present series, the dopamine D2-receptor agonists have the S-configuration at the nitrogen-bearing carbon (C2), whereas the only established D2-receptor antagonist, 1S,2R-5-hydroxyl-1-methyl-2-(di-n-propylamino)tetralin (1S,2R-UH-242), has the opposite absolute configuration at C2. Two conformational parameters, the tetralin inversion angle (phi) and the dihedral angle tau(C1, C2, N, N-H or electron pair) (tau N), are shown to be critical for D2-receptor agonism; phi values around 0 degrees and tau N values around 60 degrees appear to be optimal. The low D2-affinity of 1S,2S-5-hydroxyl-1-methyl-2-(di-n-propylamino)tetralin seems to be related to its inability to assume a low-energy "D2-receptor agonistic conformation." It is noted that the common structural denominator between the D2-receptor antagonists 1S,2R-UH-242 and 6aS-apomorphine is their inability to assume "dopamine D2-receptor agonistic nitrogen electron pair orientations."

Apomorphine↗