Search PubMed⌕ Search

Biomedical subjects

P Skolnick

Publications and source records attributed to P Skolnick.

At least 325 records · Page 18Linked to original sources
PubMed1982

Comparative neuropharmacology of antianxiety drugs.

Over the past five years, the mechanisms of action of several classes of antianxiety drugs have been clarified. Benzodiazepines, triazolopyridazines, and barbiturates seem to produce their anxiolytic effects by interacting with a specific high affinity receptor (viz. benzodiazepine receptor) in the brain. The benzodiazepine receptor is functionally and perhaps structurally coupled to a receptor for the major inhibitory neurotransmitter GABA as well as a chloride channel or ionophore. Taken together, this receptor "complex" may mediate the behavioral effects of a number of chemically diverse antianxiety agents. Evidence for the role of the benzodiazepine-GABA receptor-chloride ionophore complex inthe mechanism of action of minor tranquilizers and a possible interaction with the novel anxiolytic buspirone is discussed.

Animals↗
PubMed1982

Beta-carbolines: synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors.

We have prepared a series of tetrahydro-beta-carbolines (TH beta C), beta-carbolines (beta-C), and other nitrogen heterocycles and evaluated them in vitro with respect to their ability to bind to benzodiazepine receptors. The fully aromatic beta-C's were more potent than their corresponding TH beta C derivatives. When substituents possessing a carbonyl (CO2Me, COCH3, CHO) were introduced at the beta-C 3-position the in vitro potency was augmented. Alcohol substituents (CH2OH, CHOHCH3) demonstrated decreased in vitro potency. The importance of the carbonyl moiety was further demonstrated when beta-carboline-3-carboxylic acid was shown to bind tighter to benzodiazepine receptors at lower pH. A lower pH increases the concentration of the acid and decreases the concentration of the anion. 3-(Hydroxymethyl)-beta-carboline (24), 3-formyl-beta-carboline (25) and 3-acetyl-beta-carboline (27) were benzodiazepine antagonists in vivo. Methyl isoquinoline-3-carboxylate (31a) also had in vitro activity. The same structure-activity relationships seen in beta-C's were also observed for isoquinolines.

Animals↗
PubMed1982

High-affinity binding of [3H]desipramine to rat brain: a presynaptic marker for noradrenergic uptake sites.

High-affinity binding sites (apparent KD = 1.5 nM) for [3H]desipramine have been demonstrated and characterized in membranes prepared from rat brain. The binding of [3H]desipramine was found to be saturable, reversible, heat-sensitive, sodium-dependent, and regionally distributed among various regions of the brain. High concentrations of [3H]desipramine binding sites were found in the septum, cerebral cortex, and hypothalamus, whereas lower concentrations were found in the medulla, cerebellum, and corpus striatum. A very good correlation (r = 0.81, P less than 0.001) was observed between the potencies of a series of drugs in inhibiting high-affinity [3H]desipramine binding and their capacity to block norepinephrine uptake into synaptosomes. In 6-hydroxydopamine-lesioned rats there was a marked decrease in [3H]norepinephrine uptake and [3H]desipramine binding with no significant alterations in either [3H]serotonin uptake or [3H]imipramine binding. These results suggest that the high-affinity binding of [3H]desipramine to rat brain membranes is pharmacologically and biochemically distinct from the high-affinity binding of [3H]imipramine, and that there is a close relationship between the high-affinity binding site for [3H]desipramine and the uptake site for norepinephrine.

Animals↗
PubMed1982

Inhibition of [3H]diazepam and [3H]3-carboethoxy-beta-carboline binding by irazepine: evidence for multiple "domains" of the benzodiazepine receptor.

The binding of [3H]diazepam and [3H]3-carboethoxy-beta-carboline was examined in rat brain synaptosomal membranes treated with irazepine, an alkylating benzodiazepine. Under incubation conditions that resulted in a 25-33% reduction in the Bmax of [3H]diazepam binding, only modest (less than 8.5%) reductions in the Bmax of [3H]3-carboethoxy-beta-carboline were observed. The differential effects of irazepine on the binding of these two compounds may be explained by the presence of multiple areas or "domains" on the benzodiazepine receptor.

Animals↗
PubMed1982

Biological substrates of anxiety: benzodiazepine receptors and endogenous ligands.

Benzodiazepines have been shown to produce most, if not all, of their pharmacological effects by directly interacting with specific recognition or receptor sites within the CNS. The presence of benzodiazepine receptors has prompted many studies as to their possible physiological significance, including attempts at isolating an endogenous ligand. To data a number of substances including the purines inosine and hypoxanthine, nicotinamide, beta-carbolines, and an unidentified peptide factor have been isolated and postulated as being endogenous ligands. A number of these compounds have also been shown to either mimic or antagonize the behavioral effects of benzodiazepines, although it is still unclear whether these occur under physiological conditions. More recent biochemical studies have established a functional (and perhaps structural) relationship between te benzodiazepine receptor and the receptor for gamma amino butyric acid (GABA), the major inhibitory neurotransmitter in brain. It now appears that the benzodiazepine receptor actually exists as a "supramolecular complex" consisting of a GABA receptor and an associated chloride channel. A number of anxiolytic drugs including the barbiturates and pyrazolopyridines appear to act through these associated "regulatory" sites rather than directly on the benzodiazepine recognition site.

Animals↗
PubMed1982

Buspirone: chemistry, pharmacology, and behavior.

Recent neurochemical and behavioral observations with the nonbenzodiazepine anxiolytic buspirone raise several issues of importance to neuroscientists. These include: (1) the role of a GABA-benzodiazepine receptor-chloride ionophore complex in the actions of buspirone and other anxiolytics; (2) the involvement of dopaminergic pathways in mediating anxiety and/or anxiolytic actions; and (3) the existence of a common pre- or postreceptor "effector system" for buspirone and other antianxiety agents. These issues are critically discussed in light of recent findings.

Animals↗
PubMed1981

Pentobarbital: dual actions to increase brain benzodiazepine receptor affinity.

The binding of [3H]diazepam to benzodiazepine receptors was studied in extensively washed membranes of rat cerebral cortex in the presence of the depressant barbiturate, pentobarbital. Pentobarbital, like the endogenous neurotransmitter gamma-aminobutyric acid (GABA), increased the basal binding and also potentiated the GABA-enhanced binding of [3H]diazepam to benzodiazepine receptors by increasing the apparent affinity of [3H]diazepam for the benzodiazepine receptor. The concentrations of pentobarbital necessary to elicit these effects in vitro are the same as those observed after treatment with pharmacologically relevant doses, suggesting that a common neurochemical association may exist between these types of compounds.

Animals↗