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A Malmberg

Publications and source records attributed to A Malmberg.

28 records · Page 2Linked to original sources
PubMed1995

Why does clozapine stimulate the motor activity of reserpine-pretreated rats when combined with a dopamine D1 receptor agonist?

The aim of the present experiments was to investigate the locomotor stimulant effects of the atypical antipsychotic agent, clozapine, in rats depleted of their dopamine by reserpine and alpha-methyl-p-tyrosine pretreatment. Clozapine itself induced a slight but never significant stimulation of locomotor activity which was enhanced by the addition of the selective dopamine D1 receptor agonist, SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3- benzazepine), but not by the selective dopamine D2 receptor agonist, quinpirole. The stimulation produced by clozapine plus SKF38393 was blocked by the selective dopamine D1 receptor antagonist, SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzapine hydrochloride), while the selective dopamine D2 receptor antagonist, haloperidol, was ineffective. A combination of SCH23390 and haloperidol blocked the clozapine plus SKF38393-induced locomotion. Unlike clozapine, neither the selective 5-HT2 receptor antagonist, ritanserin, nor the dopamine D2 receptor antagonists, haloperidol and remoxipride, caused locomotor activation when given alone or in combination with SKF38393. The indirectly acting sympathomimetic amine, d-amphetamine, was inactive in the monoamine-depleted rats, indicating that no dopamine was available for release by d-amphetamine. The muscarinic receptor antagonist, scopolamine, alone did not alter locomotion, but produced marked stimulation when combined with SKF38393 but not with quinpirole. This stimulation was not affected by haloperidol. However, the scopolamine plus SKF38393-induced stimulation was partially blocked by SCH23390 or by a combination of haloperidol and SCH23390. The data indicate that clozapine, in rats depleted of their dopamine stores, exhibits properties consistent with those of a dopamine receptor agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Are there neurological and sensory risk factors for schizophrenia?

The association between left-handedness, epilepsy, and hearing impairment with schizophrenia was investigated using data from a cohort of 50,000 male Swedish conscripts linked to the Swedish National Register of Psychiatric Care. Though epilepsy was rare in this cohort, no association with schizophrenia was found. Left-handedness was associated with neither schizophrenia nor other psychoses. The study shows that, when studied from a population base, the apparent increase in neurodevelopmental anomalies in schizophrenia may be an artefact of bias. However, schizophrenia was 1.81 (95% CI 1.2-2.7) times higher amongst those with severe hearing loss, which may be preventable.

Adolescent↗
PubMed1995

Characterization of [3H]quinpirole binding to human dopamine D2A and D3 receptors: effects of ions and guanine nucleotides.

The in vitro receptor binding characteristics of [3H]quinpirole to cloned human dopamine D2A (long isoform) and D3 receptors were investigated and compared with those of rat striatal dopamine receptors. [3H]Quinpirole selectively labeled the high-affinity state of cloned dopamine D2A and striatal D2 receptors with an affinity of about 4 nM. In the striatum, [3H]quinpirole bound to 70% of the receptors labeled by the antagonist [3H]raclopride, whereas the corresponding value for cloned dopamine D2A receptors was 26%. [3H]Quinpirole labeled both the high- and "low-"affinity states of the dopamine D3 receptor with the affinities of 0.6 nM (36% of the receptors) and 7.3 nM, respectively. At all three receptors, sodium decreased the proportion of receptors labeled by [3H]quinpirole, whereas its affinity for the remaining high-affinity sites was not changed. Further addition of guanine nucleotides completely converted the high-affinity binding into low. Thus, even the dopamine D3 receptor was regulated by sodium and guanine nucleotides. Competition studies for [3H]quinpirole and [3H]raclopride binding revealed that the agonists (+)-(R)-7-hydroxy-2-dipropylaminotetralin and quinpirole, previously claimed to be highly dopamine D3-selective (approximately 100-fold), displayed high affinity for the high-affinity agonist states of both dopamine D2 and D3 receptors. When these values were compared, instead of the apparent affinities from the one-site analysis, the dopamine D3-selectivities were 20-fold for (+)-(R)-7-hydroxy-2-dipropylaminotetralin and 8-fold for quinpirole. Thus, it is of importance to consider both high- and low-affinity agonist states when receptor selectivities are evaluated.

Animals↗
PubMed1994

Molecular basis for the binding of 2-aminotetralins to human dopamine D2A and D3 receptors.

The affinities of a series of stereochemically well defined 2-aminotetralin derivatives for cloned human dopamine D2A (443 amino acids) and D3 receptors expressed in mammalian cell lines have been determined using [3H]raclopride as radioligand. Several of the compounds tested showed high selectivity for the D3 receptor. Notably, (R)-7-hydroxy-2-dipropylaminotetralin displayed 70-fold selectivity for the D3 receptor and its cis-C1-methyl analog, (1S,2R)-AJ-148, displayed 38-fold selectivity. Large differences in receptor binding affinities between the compounds were obtained, despite the close structural relationship of the compounds. To better understand the receptor interactions of these compounds, we have constructed homology-based receptor models of the human D2A and D3 receptors by using bacteriorhodopsin as a template. The resulting model was used in conjunction with an indirect model. The indirect model describes a proposed active agonist conformation for dopaminergic 2-aminotetralins and related compounds and consists of a receptor excluded volume that was used to define the agonist binding site. We docked a number of ligands into the D2A and D3 binding sites by optimizing attractive interactions and minimizing repulsive interactions. In the binding site model of the D2A receptor, the protonated nitrogen of the ligands interacts with Asp-114 in transmembrane region (TM) 3 through a reinforced ionic bond. The aspartic acid is surrounded by aromatic residues that may stabilize the ion pair formed with the protonated ligands. In addition, a hydrogen bond is formed from the phenolic hydrogen of the agonist ligands to Ser-193 (TM 5). Aromatic edge-to-face interactions occur between Phe-390 (TM 6) and the aromatic ring of the agonists. 2-Aminotetralin-based dopaminergic antagonists [e.g., (1S,2R)-UH-232] structurally related to agonists have a different but partly overlapping mode of binding, with the aromatic ring located more extracellularly, compared with agonists. The structure-activity relationships that are apparent from this and previous studies are qualitatively rationalized by the binding site models.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Binding characteristics of remoxipride and its metabolites to dopamine D2 and D3 receptors.

The substituted benzamide, remoxipride, is a new atypical antipsychotic agent with good clinical efficacy and low extrapyramidal side-effect potential. In the present study, the in vitro receptor binding properties of remoxipride and several of its metabolites to rat striatal dopamine D2 and cloned human dopamine D2A and D3 receptors were investigated. Remoxipride bound to [3H]raclopride-labelled dopamine D2 receptors in rat striatum with an affinity (Ki) of 113 nM. The significantly lower affinities of remoxipride reported when [3H]spiperone was used as a radioligand are suggested to be due to methodological problems associated with the use of very high-affinity radioligands. Some of the phenolic metabolites of remoxipride found mainly in rat exhibited considerably higher affinities to dopamine D2 and D3 receptors than remoxipride itself. The pyrrolidone metabolites found mainly in the human had very low dopamine D2 and D3 affinities. The present in vitro results suggest that the behavioural effects of remoxipride in rats may reflect the effect of remoxipride and some of its high-affinity metabolites.

Animals↗
PubMed1993

Unique binding characteristics of antipsychotic agents interacting with human dopamine D2A, D2B, and D3 receptors.

In the present study we have compared the pharmacological properties of human dopamine (DA) D2A, D2B, and D3 receptors expressed in mammalian cell lines, using [3H]raclopride as a radioligand. Most of the compounds tested had about equal affinity for D2A and D3 receptors, with the exception of remoxipride, which displayed a 10-fold D2 selectivity, and the aminotetralin (+)-UH 232, which displayed a 5-fold D3 selectivity. Several antipsychotic agents, including clozapine and substituted benzamides, bound with 2-3-fold higher to the D2B (short) than to the D2A (long) isoform, whereas others failed to differentiate between the two isoforms. The atypical antipsychotic agent clozapine bound in a biphasic manner and with unexpectedly high affinity (35 nM) to the D2B receptor, suggesting that clozapine may not be as D4 selective as reported previously. In addition, remoxipride, a new antipsychotic agent with low potential to produce extrapyramidal side effects, displayed 2-3-fold higher affinity for the D2B receptor than for the D2A receptor. Furthermore, sodium differently regulated clozapine and benzamide binding to the various DA receptor subtypes. Thus, sodium decreased the affinity of clozapine for D2A and D2B receptors about 3-fold, whereas the affinity for D3 receptors was unaltered. In contrast, the affinity of raclopride for the three DA receptor subtypes was increased by sodium. Whether the unique characteristics of the binding of clozapine and benzamides to cloned DA receptors demonstrated in the present study are related to the favorable clinical properties of these compounds remains to be elucidated.

Animals↗
PubMedDate not supplied

In vitro receptor binding characteristics of the new dopamine D2 antagonist [125I]NCQ-298: methodological considerations of high affinity binding.

The substituted benzamide [125I]NCQ-298 is a recently developed radioligand that has been shown to bind with high affinity and selectivity to dopamine D2 receptors. The present studies were designed to optimize the in vitro receptor binding method of [125I]NCQ-298 and to determine whether it labels the same receptor population as the widely used benzamide [3H]raclopride. Rat striatal D2 receptors and cloned human D2 and D3 receptors were used. We found that due to the high affinity of [125I]NCQ-298 (Kd approximately 20 pmol/l), long incubation time (4 hrs at 30 degrees C) and low receptor concentration (approximately 2 pmol/l) were necessary in order to reach equilibrium and avoid ligand depletion. The optimal composition of the incubation buffer for rat striatal [125I]NCQ-298 binding assays was (in mM): 50 Tris-HCI, 120 NaCl, 5 KCl, 1 MgCl2, 0.01 pargyline, 0.1 EDTA, 0.05 protease inhibitors (PMSF and bacitracin) and 0.01% ascorbic acid. It is concluded that, when studied under correct experimental conditions, [125I]NCQ-298 is an excellent high-affinity D2 receptor radioligand which labels the same receptor population as [3H]raclopride (Bmax values; 32 +/- 3 and 36 +/- 1 pmol/g w.w., respectively).

Animals↗