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Biomedical subjects

A M Johansson

Publications and source records attributed to A M Johansson.

At least 19 recordsLinked to original sources
PubMed2002

Active immunization against nicotine suppresses nicotine-induced dopamine release in the rat nucleus accumbens shell.

BACKGROUND: Tobacco smoking is the largest preventable cause of morbidity and premature mortality in the world. Although its medical consequences are well documented, 20-50% of the population even in developed countries remain tobacco smokers. The drugs presently used in smoking cessation have limited efficiency and, therefore, there is a need for alternative and improved treatments. One novel approach in this regard may be provided by immunization against nicotine. OBJECTIVE: The present study in male Wistar rats investigated if active immunization with a novel nicotine immunogen, IP18-KLH, may generate nicotine-selective antibodies and, furthermore, whether this treatment might prevent nicotine from exerting its stimulating effect on the mesolimbic, dopaminergic reward system in the brain. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to determine the titer of nicotine antibodies in plasma after immunization with IP18-KLH in Freund's adjuvant. Competitive ELISA was used to assess the selectivity of the antibodies. Finally, we used in vivo voltammetry to investigate whether active immunization with IP18-KLH could prevent nicotine-induced dopamine release in the shell of nucleus accumbens (NAC(shell)). RESULTS: The present study shows that active immunization with IP18-KLH generates antibodies that are highly selective for nicotine. Furthermore, immunization with IP18-KLH prevented the nicotine-induced increase in dopamine release in the NAC(shell), a biochemical correlate to the rewarding properties of nicotine. CONCLUSIONS: Active immunization with IP18-KLH prevents a central effect of nicotine that is considered critical for the induction of nicotine dependence. Consequently, active immunization may provide long-term protection against initiation of tobacco dependence, an effect that may prove particularly advantageous in relapse prevention.

Animals↗
PubMed2002

Active immunization against nicotine prevents reinstatement of nicotine-seeking behavior in rats.

BACKGROUND: The presently available pharmaceutical aids in smoking cessation possess a rather limited effectiveness. Therefore, we have synthesized a series of immunoconjugates that stimulate the induction of antibodies which may bind nicotine in the blood, thereby preventing it from passing the blood-brain barrier. Thus, the reinforcing action of nicotine in the brain, which is the driving force in tobacco smoking, should be abolished. OBJECTIVE: The present study was undertaken to test this notion in a long-term relapse model in rats, measuring the reinstatement of nicotine-seeking behavior, following active immunization with IP18-KLH, one of our immunoconjugates. METHODS: Male Wistar rats were immunized with a nicotine-KLH conjugate (nicotine immunogen) and Freund's adjuvant after having been trained to meet the criteria of stable nicotine self-administration on a fixed ratio (FR3) schedule. The rats were subsequently extinguished from nicotine self-administration behavior and finally, as extinction was completed, they were exposed to small, priming doses of nicotine, which previously have been shown to reinstate the nicotine-seeking behavior. The antibody titers were measured by ELISA. RESULTS: It was found that rats with high titers (>1:10,000) of antibodies against nicotine, in contrast to those with low/no nicotine selective antibodies, do not reinstate nicotine self-administration behavior when they are exposed to nicotine. CONCLUSIONS: Our findings indicate that active immunization against nicotine may effectively abolish the reinforcing action of nicotine in brain, an effect which is critical for relapse in nicotine dependence. These data suggest the potential utility of active immunization in smoking cessation programs.

Animals↗
PubMed2001

Serotonergic and dopaminergic activities of rigidified (R)-aporphine derivatives.

Novel rigidified (R)-aporphine derivatives were synthesized from (R)-1,11-carbonylaporphine by ring expansion reactions. The structures of the novel analogues were assigned by NMR spectroscopy and X-ray crystallography. The compounds showed moderate affinities and selectivities at serotonin S-HT1A and 5-HT7 and dopamine D2A receptors.

Animals↗
PubMed2001

Sympathetic skin vasoconstriction--further evaluation using laser Doppler techniques.

The aim of this study was to quantify the reflex sympathetic vasoconstriction in skin at different depths. Twenty healthy subjects were studied. Finger skin blood flow was measured using laser Doppler perfusion imaging (LDPI) and laser Doppler perfusion monitoring (LDPM). In LDPM, a probe with fibres separated 0.25 mm (deep) and 0.14 mm (superficial) from the illuminating fibre was used. Local heating (40 degrees C) was achieved with a Peltier element, and reflex vasoconstriction induced by immersion of the contra-lateral hand and forearm for 3 min in water at 15 degrees C. The change in skin blood flow was measured and a vasoconstriction index (VAC: cooling/before cooling) calculated. VAC indices of LDPI, LDPM-0.25 and LDPM-0.14 were 0.60, 0.59 and 0.60, respectively. The two components of the LDPM perfusion value, blood cell velocity and concentration, were studied separately. Their contributions in LDPM-0.25 were roughly the same, whereas the velocity component dominated in LDPM-0.14, although their relative responses in the two channels were similar. We conclude that sympathetic skin vasoconstriction does not significantly differ in two compartments, as probed with fibres separated by 0.25 and 0.14 mm. Blood cell velocity is influenced in a proportional way, as is concentration.

Adult↗
PubMed2000

Derivatives of (R)-1,11-methyleneaporphine: synthesis, structure, and interactions with G-protein coupled receptors.

The design and synthesis of a well-characterized novel ring system, (R)-lambda1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda1,11-carbonylaporphine [(R)-11] or to the 1,11-hydroxymethyleneaporphine epimers gave separable mixtures of epimers. The epimeric ratios obtained in most reactions seem to be a result of steric factors directing the nucleophilic attack. The structure of the epimers was determined by a combination of X-ray crystallography (5 derivatives), NMR spectroscopy, and chemical correlation. Interesting and diverse pharmacological profiles of the derivatives were revealed through binding studies at serotonin 5-HT(7) and 5-HT(1A) receptors as well as at dopamine D(2A) receptors. Two derivatives appeared to be selective 5-HT(7) receptor antagonists. It is evident from our results that the novel ring system [(R)-4] provides a useful complement to other scaffolds available to medicinal chemists involved in studies of GPC receptors.

Animals↗
PubMed2000

Effect of multiple serine/alanine mutations in the transmembrane spanning region V of the D2 dopamine receptor on ligand binding.

Three conserved serine residues (Ser193, Ser194, and Ser197) in transmembrane spanning region (TM) V of the D2 dopamine receptor have been mutated to alanine, individually and in combination, to explore their role in ligand binding and G protein coupling. The multiple Ser -->Ala mutations had no effect on the binding of most antagonists tested, including [3H]spiperone, suggesting that the multiple mutations did not affect the overall conformation of the receptor protein. Double or triple mutants containing an Ala197 mutation showed a decrease in affinity for domperidone, whereas Ala193 mutants showed an increased affinity for a substituted benzamide, remoxipride. However, dopamine showed large decreases in affinity (>20-fold) for each multiple mutant receptor containing the Ser193Ala mutation, and the high-affinity (coupled) state of the receptor (in the absence of GTP) could not be detected for any of the multiple mutants. A series of monohydroxylated phenylethylamines and aminotetralins was tested for their binding to the native and multiple mutant D2 dopamine receptors. The results obtained suggest that Ser193 interacts with the hydroxyl of S-5-hydroxy-2-dipropylaminotetralin (OH-DPAT) and Ser197 with the hydroxyl of R-5-OH-DPAT. We predict that Ser193 interacts with the hydroxyl of R-7-OH-DPAT and the 3-hydroxyl (m-hydroxyl) of dopamine. Therefore, the conserved serine residues in TMV of the D2 dopamine receptor are involved in hydrogen bonding interactions with selected antagonists and most agonists tested and also enable agonists to stabilise receptor-G protein coupling.

Alanine↗
PubMed1999

Derivatives of (R)-2-amino-5-methoxytetralin: antagonists and inverse agonists at the dopamine D2A receptor.

A series of N-arylmethyl substituted (R)-5-methoxy-2-(propylamino)tetralins has been prepared and evaluated for affinity and efficacy at dopamine (DA) D2A receptors. The novel compounds appeared to be antagonists or inverse agonists. (R)-2-[(Benzyl)propylamino]-5-methoxytetralin (7) was characterized as a potent inverse agonists at DA D2A receptors in a [35S]GTPgammaS binding assay.

Dopamine Antagonists↗
PubMed1999

Novel derivatives of 3-(dipropylamino)chroman. Interactions with 5-HT1A and D2A receptors.

Novel 8-aryl and 8-aroyl substituted derivatives of 3-(dipropylamino)chroman are described. The compounds have been prepared by a palladium catalyzed reaction of iodoarenes and a stannylated derivative of [eta6-3-(dipropylamino)chroman]Cr(CO)3. Several of the compounds have high affinity for 5-HT1A receptors whereas the affinity for D2A receptors is lower, the 8-arylated derivatives being slightly more potent than the 8-aroylated analogues.

Animals↗
PubMed1998

Interactions of ligands with active and inactive conformations of the dopamine D2 receptor.

The affinities of 19 pharmacologically diverse dopamine D2 receptor ligands were determined for the active and inactive conformations of cloned human dopamine D2 receptors expressed in Ltk cells. The agonist [3H]quinpirole was used to selectively label the guanine nucleotide-binding protein-coupled, active receptor conformation. The antagonist [3H]raclopride, in the presence of the non-hydrolysable GTP-analogue Gpp(NH)p and sodium ions and in the absence of magnesium ions, was used to label the free inactive receptor conformation. The intrinsic activities of the ligands were determined in a forskolin-stimulated cyclic AMP assay using the same cells. An excellent correlation was shown between the affinity ratios (KR/KRG) of the ligands for the two receptor conformations and their intrinsic activity (r=0.96). The ligands included eight structurally related and enantiopure 2-aminotetralin derivatives; the enantiomers of 5-hydroxy-2-(dipropylamino)tetralin, 5-methoxy-2-(dipropylamino)tetralin, 5-fluoro-2-(dipropylamino)tetralin and 2-(dipropylamino)tetralin. The (S)-enantiomers behaved as full agonists in the cyclic AMP assay and displayed a large KR/KRG ratio. The (R)-enantiomers were classified as partial agonists and had lower ratios. The structure-affinity relationships of these compounds at the active and the inactive receptor conformations were analysed separately, and used in conjunction with a homology based receptor model of the dopamine D2 receptor. This led to proposed binding modes for agonists, antagonists and partial agonists in the 2-aminotetralin series. The concepts used in this study should be of value in the design of ligands with predetermined affinity and intrinsic activity.

Cells, Cultured↗
PubMed1998

Rapid increase in diagnosis of cutaneous melanoma in situ in Sweden, 1968-1992.

We analyzed incidence trends of cutaneous melanoma in situ in Sweden in 1968-1992. Among men, age-standardized rates increased from 0.1/100,000 in 1968 to 2.9/100,000 in 1992, which corresponds to an average annual increase of 15.0%. Among women, rates increased from 0.3 to 3.7, and the annual increase was 12.8%. Age-specific rates increased since 1978, predominantly in men aged 45 years and older, whereas in women rates increased in all ages. Multivariate analysis showed that incidence rates could be explained by both cohort effects and period effects in addition to age. However, cohort effects seemed more important among men than among women, in whom period effects dominated. Thus, factors associated with the development of melanoma in situ may differ between the sexes. Melanoma in situ is an immediate precursor of invasive melanoma, and the increased detection and surgical excision of these tumors will prevent the occurrence of invasive melanoma.

Adolescent↗
PubMed1997

Trends in urinary bladder cancer incidence in Sweden 1960-93 with special reference to histopathology, time period, birth cohort, and smoking.

This study investigates the incidence trends of urinary bladder cancer in Sweden from 1960 through 1993 (a total of 46,211 cases). Age-standardized incidence rates increased among men from 14.6 per 10(5) in 1960 to 33.5 in 1993 and among women from 4.8 to 8.8, corresponding to an average annual increase of 2.4 percent (95 percent confidence interval [CI]) = 2.0-2.7 percent) and 1.1 percent (CI = 0.9-1.4 percent), respectively. The largest increase occurred in the oldest age-groups. The proportion of patients with transitional cell carcinoma increased in men from 66.0 percent in 1960-64 to 93.6 percent in 1990-93 and in women from 61.0 percent to 89.4 percent. The proportion of patients with papillomas decreased, whereas those with adenocarcinoma and squamous cell carcinoma were stable. Regression modeling (based on the period 1960-89) showed a strong linear effect due to either period and/or cohort. Among men, additional non-linear effects by both period and cohort were obtained. The cohort effects were more important. Cohort data on having smoked daily showed considerable similarities with the estimated cohort-effects. Our findings suggest that the increase of tobacco smoking in successive generations can explain the increase in incidence rates of bladder cancer in Sweden, whereas improved diagnostic activities and registration are less likely to explain fully the changes in incidence rates.

Adult↗
PubMed1996

Novel (R)-2-amino-5-fluorotetralins: dopaminergic antagonists and inverse agonists.

A series of secondary and tertiary N-alkyl derivatives of (R)-2-amino-5-fluorotetralin have been prepared. The affinities of the compounds for [3H]raclopride-labeled cloned human dopamine (DA) D2 and D3 receptors as well as [3H]-8-OH-DPAT-labeled rat hippocampal 5-HT1A receptors were determined. In order to selectively determine affinities for the high-affinity agonist binding site at DA D2 receptors, the agonist [3H]quinpirole was used. The intrinsic activities of the compounds at DA D2 and D3 receptors were evaluated in a [35S]GTP gamma S binding assay. The novel compounds were characterized as dopaminergic antagonists or inverse agonists. The antagonist (R)-2-(butylpropylamino)-5-fluorotetralin (16) bound with high affinity (Ki = 4.4 nM) to the DA D3 receptor and was the most D3-selective compound (10-fold). (R)-2-[[4-(8-Aza-7, 9-dioxospiro[4.5]decan-8-yl)butyl]propylamino]-5-fluorote tralin (18) bound with very high affinity to both DA D3 and 5-HT1A receptors (Ki = 0.2 nM) and was also characterized as a dopaminergic antagonist. (R)-2-(Benzylpropylamino)-5-fluorotetralin (10) behaved as an inverse agonist at both DA D2 and D3 receptors. It decreased the basal [35S]GTP gamma S binding and potently inhibited the DA-stimulated [35S]GTP gamma S binding. It is apparent that the intrinsic activity of a 2-aminotetralin derivative may be modified by varying the N-alkyl substituents.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Derivatives of (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: synthesis and interactions with 5-HT1A receptors.

Analogs of the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-1,(S)-UH301] have been prepared. The C8-substituent has been varied, and in some derivatives one of the N-propyl groups has been exchanged for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)-butyl group. The novel compounds have been evaluated for affinity to rat brain 5-HT1A receptors in competition experiments with [3H]-8-OH-DPAT. In addition, the efficacy of the compounds was assessed by their ability to inhibit the VIP-stimulated cAMP formation in GH4ZD10 cells expressing rat 5-HT1A receptors. Varying degrees of intrinsic activity was revealed among the compounds tested, i.e., the profiles ranged from full agonists to antagonists. All R-enantiomers are characterized as full agonists at 5-HT1A receptors, whereas partial agonists or antagonists were found among the corresponding S-enantiomers. Substitution of one of the N-propyl groups for a 4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group seems to increase efficacy as well as affinity for 5-HT1A receptors. A favorable interaction with an accessory binding site by the N-4-(8-aza-7,9-dioxospiro[4.5]decan-8-yl)butyl group may contribute to the increased affinity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

10-substituted 11-oxygenated (R)-aporphines: synthesis, pharmacology, and modeling of 5-HT1A receptor interactions.

Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".

Animals↗
PubMed1996

11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.

A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].

Animals↗
PubMed1996

Synthesis and pharmacology of the enantiomers of UH301: opposing interactions with 5-HT1A receptors.

The (S)-enantiomer of 5-fluoro-8-hydroxy-2-(dipropylamino) tetralin [(S)-2a; (S)-UH301] was the first reported 5-HT1A receptor antagonist. We now give a full account on the synthetic effort leading to the preparation of the racemate and the enantiomers of 2a. The crystal and molecular structure of 2a. HBr has been determined by X-ray diffraction and the absolute configuration has been deduced using statistical tests of the crystallographic R values. The unit cell is tetragonal (P4(1)2(1)2) with a = b = 13.2235(2), c = 39.560(1) A and contains two crystallographically independent molecules in each asymmetric unit. The two solid state conformers differ in the conformation of the N-propyl groups. The pharmacological characterization of the enantiomers was done by use of in vivo biochemical and behavioural assays in rats. The (R)-enantiomer of 2a is a 5-HT1A receptor agonist of low potency while (S)-2a does not exhibit any agonist properties at 5-HT1A receptors. As a consequence of the opposing effects of the enantiomers, the racemate, rac-2a, does not produce any clear-cut effects in rats. The reduced efficacy of (S)-2a as compared to the well known 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino) tetralin (1;8-OH-DPAT) may be due to the fluoro-substituent induced negative potential of the aromatic ring.

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