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C Braestrup

Publications and source records attributed to C Braestrup.

At least 19 recordsLinked to original sources
PubMed1992

NNC-112, NNC-687 and NNC-756, new selective and highly potent dopamine D1 receptor antagonists.

The neurochemical properties of three novel benzazepine derivatives NNC-112, NNC-687 and NNC-756 were assessed. These compounds inhibited dopamine D1 receptor binding in vitro with low nanomolar to picomolar dissociation constants whereas those for the D2 receptor were in the micromolar range. Contrary to classical neuroleptics, but similar to the atypical neuroleptics, clozapine and fluperlapine, NNC-112, NNC-687 and NNC-756 were relatively more potent in inhibiting dopamine-stimulated adenylyl cyclase than [3H]SCH 23390 binding. Both NNC-112 and NNC-756 had high affinity for the 5-HT2 receptor whereas NNC-687 had low affinity for this receptor. The affinity for other receptors or neurotransmitter transporters was very low. In vivo, the dopamine D1 receptor selective profile of NNC-112, NNC-687 and NNC-756 was evident from the potent inhibition of D1 receptor binding whereas no effect on D2 receptor binding was apparent. In addition, the compounds blocked D1 receptor-mediated rotation in unilaterally 6-hydroxydopamine-lesioned rats, but had no effect on D2-induced rotation. Thus, NNC-112, NNC-687 and NNC-756 are potent and selective dopamine D1 receptor antagonists that may be useful in the treatment of schizophrenia.

Animals↗
PubMed1992

In vivo labeling of the central GABA uptake carrier with 3H-Tiagabine.

The in vivo binding of 3H-Tiagabine to the central GABA uptake carrier in mouse brain was characterized. 3H-Tiagabine in vivo bound to a single class of binding sites with a Kd = 72.5 nM and a Bmax = 640 pmol/g tissue. 3H-Tiagabine binding in vivo was regionally distributed within the CNS, and showed a good correlation with 3H-Tiagabine binding in vitro. Pharmacological characterization of 3H-Tiagabine binding in vivo revealed a binding site exhibiting specificity for GABA uptake inhibitors. Experiments examining the in vivo receptor occupancy of the GABA uptake carrier for a series of GABA uptake inhibitors revealed that 20-30% of the GABA uptake sites were occupied at the ED50 for inhibiting DMCM-induced clonic convulsions, while a 50-62% receptor occupancy in vivo was needed to inhibit rotarod performance. These data suggest that 3H-Tiagabine in vivo binding may be a useful method for assessing GABA uptake inhibitor penetration into the CNS, and may be a useful tool for studying the physiological regulation of the GABA uptake carrier.

Animals↗
PubMed1992

Introductory comments: a brief history of the development of paroxetine.

In the late 1960s research was begun to develop antidepressant agents that would be selective inhibitors of serotonin reuptake. The antidepressants then available, the tricyclic antidepressants, inhibited the reuptake not only of serotonin but also of other monoamines such as noradrenaline--and it is this activity, together with anticholinergic actions, that is responsible for many of the adverse effects such as cardiac toxicity. After much chemical research a family of antidepressants with similar pharmacological activity but disparate chemical structure was developed by several medicinal research laboratories. Because the selective serotonin reuptake inhibitors are chemically different they do not possess the common structural side-effect profile of the tricyclic antidepressants.

Paroxetine↗
PubMed1979

Benzodiazepine receptors in the brain as affected by different experimental stresses: the changes are small and not undirectional.

Rats and mice were exposed to several different stress situations to investigate whether brain benzodiazepine receptors were sensitive to altered external or internal environmental circumstances. All stresses were applied for several days. Electrical foot shock and post-natal isolation of newborn pups resulted in small (7--25%; P less than 0.05--0.001) decreases in benzodiazepine receptor binding in some cerebral cortex or hippocampal areas while immobilization stress resulted in a small (9%; P less than 0.05) increase in frontal cortex. Other brain areas (i.e., striatum, cerebellum, pons-medulla, and occipital cortex) and other stress forms (isolation of male mice, forced swimming in cold water, or chronic amphetamine intoxication) did not change receptor binding. The effect of prolonged stress on benzodiazepine receptors is complex and not very pronounced.

Aggression↗
PubMed1979

Some properties of brain specific benzodiazepine receptors: new evidence for multiple receptors.

Several new lines of evidence suggest the existence of two or more distinct types of benzodiazepine receptors, in contrast to earlier results suggesting the presence of only one class of receptors. Appropriate thermoinactivation experiments indicate two receptors with different thermostabilities. Several triazolopyridazines, with some of the pharmacological properties of anxiolytics have recently been shown to displace 3H-diazepam and 3H-flunitrazepam with Ki values in the 6 to 100 nanomolar range. These new substances are active in conflict tests in rats and monkeys and prevent metrazol induced seizures in vivo, but strikingly lack the ataxia and sedative properties of the benzodiazepines. Hill analyses of dose-response curves for some of these substances yields Hill coefficients in the range of 0.4--0.6, suggesting that these compounds may be able to discriminate between several types of benzodiazepine receptors.

Amino Acids↗
PubMed1979

Neuronal localisation of benzodiazepine receptors in cerebellum.

The cellular localisation of benzodiazepine receptors was studied. Kainic acid induced neuronal lesions (2 x 0.25-2 x 2 micrograms; 2-26 days in rat cerebellum decreased specific binding of [3H]flunitrazepam down to 35% of controls. Specific binding of [3H]flunitrazepam was also decreased (to 80% of controls) in the cerebllum of mutant nervous mouse (nr/nr) where Purkinje cells are degenerated but in the mutant weaver mouse where granule cells are degenerated. These results show that benzodiazepine receptors are located mainly on neurons; both on Purkinje cells and other neurons, but not to a great extent on granule cells.

Animals↗
PubMed1979

Increased thermolability of benzodiazepine receptors in cerebral cortex of a baboon with spontaneous seizures: a case report.

The benzodiazepine receptor in the cortex of 1 spontaneously epileptic baboon exhibited an increased rate of thermal inactivation at 65 degrees C when compared with those from 3 other baboons. In other respects (receptor concentration, affinities for flunitrazepam and diazepam, and response to changing pH), the benzodiazepine receptor from this animal was very similar to the receptors in the cortex of 3 other baboons. The 3H-QNB (muscarinic) and 3H-naloxone (opiate) binding sites in the brain of all 4 baboons appeared very similar with respect to all parameters studied (thermal stability, concentration, regional distribution, and affinities for respective ligands). An endogenous factor stabilizing the benzodiazepine receptor could be lacking in the spontaneously epileptic baboon.

Animals↗
PubMed1978

Pharmacological characterization of benzodiazepine receptors in the brain.

Receptors in rat brain membranes which specifically bind 3H-diazepam were characterized pharmacologically using reference substances representing several pharmacological classes of drugs. Of 28 benzodiazepines tested, several "classical" ones (diazepam, clonazepam, lorazepam, oxazepam, nitrazepam, flurazepam, bromazepam and chlorazepate) with known clinical efficacy, as well as three newer "triazolo" benzodiazepines (estazolam, U 35,005, U 31,957), one new "imidazolo" benzodiazepine, U 31,219, and one new 2-carbamoylmethylene-benzodiazepine, displaced 3H-diazepam binding at low concentrations (Ki=1--60 nM). For these benzodiazepines there was a stastically significant correlation between Ki values for displacement and ED50 (or MED) values in several pharmacological tests predictive of anxiolytic activity in man. More than 100 nonbenzodiazepines, representing 22 distinct pharmacological classes as well as 14 presumed neurotransmitters in the CNS, including 4 peptides, were much weaker as 3H-diazepam displacers (K2 greater than 0.1 nM). These results suggest that in vitro 3H-diazepam binding represents the physiologically relevant binding to hitherto unknown receptors in the CNS.

Animals↗
PubMed1978

Benzodiazepine receptor in brain.

The evidence that the brain possesses specific receptors for benzodiazepines is summarized. Further we present a series of brain lesion experiments in rats showing that specific neuronal destructions by 6-hydroxydopamine, kainic acid in the striatum, X-ray irradiation of the hippocampus, intraperitoneal 3-acetyl-pyridine or hemisection at the thalamic level do not reduce the level of benzodiazepine receptors in striatum, hippocampus, cortex or cerebellum. These results show that the benzodiazepines are not positioned on dopamine or noradrenaline terminals, cholergic or GABA-ergic neurons in the striatum, granular cells in the hippocampus or climbing fibers in the cerebellum.

Animals↗
PubMed1978

Brain specific benzodiazepine receptors.

Brain membranes from rat and human contain a single class of brain specific binding sites for pharmacologically and clinically active benzodiazepines. There is good correlation between the pharmacological effects of benzodiazepines and the affinity for the 3H-diazepam binding site. Benzodiazepine binding sites are not present on glial cells. Selective neuronal degeneration experiments in rats indicate a neuronal localization. 3H-Flunitrazepam is a very suitable ligand for affinity binding and it binds to the same class of binding sites as 3H-diazepam. Our results indicate that the in vitro 3H-diazepam and 3H-flunitrazepam binding sites are the receptors which in vivo mediate various pharmacological and clinical effects of benzodiazepines.

Animals↗