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Biomedical subjects

P Skolnick

Publications and source records attributed to P Skolnick.

At least 307 records · Page 17Linked to original sources
PubMed1983

[3H]2-Nitroimipramine: a selective "slowly-dissociating" probe of the imipramine binding site ("serotonin transporter") in platelets and brain.

Previous studies have demonstrated a close functional and structural relationship between the "high affinity" binding site for [3H]imipramine and the presynaptic and platelet uptake site(s) for serotonin. Recently we have synthesized several nitro derivatives of imipramine which have a very high affinity for the imipramine binding site and which dissociate very slowly when incubations are performed at 0-4 degrees C. In this report, we describe the characteristics of [3H]2-nitroimipramine binding to platelet and brain membranes. Our results support the relative utility of this ligand for studying the impramine binding site (serotonin transporter) since this analogue has both a higher affinity and specific activity than [3H]imipramine. [3H]2-Nitroimipramine by virtue of its extremely slow dissociation rate should be a valuable tool in subsequent characterization and purification of the serotonin uptake or transport site.

Animals↗
PubMed1983

A benzodiazepine receptor antagonist decreases sleep and reverses the hypnotic actions of flurazepam.

The benzodiazepine receptor antagonist 3-hydroxymethyl-beta-carboline, which blocks several of the pharmacological actions of benzodiazepines, induces a dose-dependent increase in sleep latency in the rat. Furthermore, at a low dose that by itself does not affect sleep, 3-hydroxymethyl-beta-carboline blocks sleep induction by a large dose of flurazepam. The benzodiazepine receptor may play a role in both the physiological regulation and pharmacological induction of sleep.

Animals↗
PubMed1983

Sedative and electroencephalographic actions of erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA): relationship to inhibition of brain adenosine deaminase.

Parenteral administration of the adenosine deaminase (ADA) inhibitor erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) results in a profound decrease in spontaneous motor activity in mice and rats. The inhibition of cortical ADA activity measured ex vivo parallels the decrease in spontaneous motor activity in a time-dependent manner. Nonetheless, a marked reduction in electroencephalographically defined sleep was observed in rats during a period when both spontaneous motor activity and ADA activity were profoundly inhibited. These data suggest that EHNA produces in rats a state of 'quiescent waking', which may be related to the observed inhibition of brain ADA activity.

Adenine↗
PubMed1983

Strain differences in susceptibility to the convulsant actions of 3-carbomethoxy-beta-carboline.

NIH mice were found to be approximately three-fold more sensitive than NIH General Purpose mice to the convulsant actions of 3-carbomethoxy-beta-carboline. The convulsant action of 3-carbomethoxy-beta-carboline has been previously demonstrated to be mediated via an interaction with C.N.S. benzodiazepine receptors. The characteristics of the benzodiazepine receptor from the two strains appeared to be identical with respect to both binding affinity and capacity for [3H]3-carbomethoxy-beta-carboline and [3H]diazepam, as well as the relative decreases in apparent receptor affinity for [3H] 3-carbomethoxy-beta-carboline in the presence of 10 microM gamma-aminobutyric acid. Although the rate of degradation of 3-carbomethoxy-beta-carboline in plasma was similar in the two strains, a marked difference in brain levels of the drug (or an active metabolite) was observed after in vivo administration. These results suggest that pharmacokinetic, rather than pharmacodynamic factors are primarily responsible for the observed strain differences in sensitivity to 3-carbomethoxy-beta-carboline.

Animals↗
PubMed1983

New concepts in the neurobiology of anxiety.

Advances in understanding the neurobiologic bases of anxiety are reviewed. The discovery of a class of compounds generically known as "benzodiazepine antagonists" has been central to much of this work. One such group of compounds, the beta-carbolines, cause convulsions, produce an anxiety-like syndrome in primates, and reduce sleep. These compounds will provide a valuable means of investigating the mechanism of action of potential anxiolytics and of drugs currently used to treat anxious patients.

Animals↗
PubMed1982

Benzodiazepine receptor-mediated experimental "anxiety" in primates.

The ethyl ester of beta-carboline-3-carboxylic acid has a high affinity for benzodiazepine receptors in the brain. In the rhesus monkey this substance produces an acute behavioral syndrome characterized by dramatic elevations in heart rate, blood pressure, plasma cortisol, and catecholamines. The effects are blocked by benzodiazepines and the specific benzodiazepine receptor antagonist Ro 15-1788. The benzodiazepine receptor may consist of several subsites or functional domains that independently recognize agonist, antagonists, or "active" antagonists such as beta-carboline-3-carboxylic acid ethyl ester. These results suggest that the benzodiazepine receptor is involved in both the affective and physiological manifestations of anxiety, and that the administration of beta-carboxylic acid ethyl ester to monkeys may provide a reliable and reproducible animal model of human anxiety.

Animals↗
PubMed1982

(+)-Amphetamine binding to rat hypothalamus: relation to anorexic potency for phenylethylamines.

Saturable and stereospecific binding sites for (+)-[3H]amphetamine were demonstrated in membrane preparations from rat brain. The density of these binding sites varies among brain regions and is highest in the hypothalamus and brainstem. Specific (+)-[3H]amphetamine binding in hypothalamus is largely confined to synaptosomal membranes, rapidly reversible, and sensitive to both heat and proteolytic enzymes. Scatchard analysis of the equilibrium binding data revealed two distinct sites with apparent affinity constants of 93 and 300 nanomoles per liter, respectively. The effects of various psychotropic drugs as well as a number of putative neurotransmitters and related agonists and antagonists in displacing specific (+)-[3H]amphetamine binding demonstrate that these binding sites are not associated with any previously described neurotransmitter or drug receptors, but are specific for amphetamine and related phenylethylamine derivatives. Furthermore, the relative affinities of a series of phenylethylamine derivatives for (+)-[3H]amphetamine binding sites in hypothalamic membranes is highly correlated to their potencies as anorexic agents. These results suggest the presence of specific receptor sites in hypothalamus that mediate the anorexic activity of amphetamine and related drugs.

Animals↗
PubMed1982

Benzodiazepines are weak inhibitors of [3H]nitrobenzylthioinosine binding to adenosine uptake sites in brain.

Saturable, specific, high affinity binding of the potent adenosine uptake inhibitor [3H]nitrobenzylthioinosine ([3H]NBI) to brain membranes has been demonstrated. In an effort to test the hypothesis that benzodiazepine action may be due to the inhibition of adenosine uptake, the inhibition of [3H]NBI binding by diazepam, clonazepam and chlordiazepoxide was tested. The benzodiazepines are very weak inhibitors of [#H]NBI binding, having IC50 values several orders of magnitude above their therapeutic levels.

Adenosine↗
PubMed1982

Effects of tetrazole derivatives on [3H]diazepam binding in vitro: correlation with convulsant potency.

A series of 8 tetrazole derivatives which differ more than one hundred-fold in their potencies as convulsants were tested for their abilities to inhibit [3H]diazepam binding to benzodiazepine receptors in vitro. The concentrations of drug necessary to inhibit 50% of specifically bound [3H]diazepam ranges from 18 micro M for undecamethylenetetrazole to 20 mM for trimethylenetetrazole. A comparison of the minimum convulsive doses for the 8 tetrazole derivatives tested with their relative potencies in displacing [3H]diazepam binding in vitro revealed a highly significant correlation (r = 0.98, P less than 0.001). In contrast, several representative tetrazole derivatives were found to have no inhibitory effects on beta-adrenergic, alpha-adrenergic or muscarinic cholinergic receptors in the same membrane preparation. These results suggest that pentamethylenetetrazole and related tetrazole derivatives may elicit their convulsant effects by interaction with the benzodiazepine receptor.

Animals↗
PubMed1982

An in vitro binding assay which differentiates benzodiazepine 'agonists' and 'antagonists'.

An in vitro test which discriminates benzodiazepine "agonists' and 'antagonists' has been developed by exploiting the apparent differences in modulation of the benzodiazepine receptor by these classes of compounds. In the presence of 10 microM GABA, the potency of benzodiazepine 'agonists' (i.e., compounds which bind to the benzodiazepine receptor with a relatively high affinity and share pharmacologic properties with benzodiazepines) to displace [3H]3-carboethoxy-beta-carboline is significantly increased. In contrast, the potency of benzodiazepine 'antagonists' (compounds which have been demonstrated to antagonize some of the pharmacologic actions of benzodiazepines) is not altered by GABA. Several chemically diverse classes of compound have been examined in this test, and within the limited number of compounds examined, this test accurately predicts 'agonist' and 'antagonist' actions in vivo.

Animals↗
PubMed1982

Interaction of barbiturates with benzodiazepine receptors in the central nervous system.

The interaction of barbiturates with benzodiazepine receptors was studied in extensively washed membrane preparations from rat brain. Sedative/hypnotic and anesthetic barbiturates such as pentobarbital, and convulsant barbiturates such as DMBB, enhanced [3H]diazepam binding in a stereospecific fashion. Freeze-thawing of membranes resulted in a decrease in the potency of barbiturates to enhance [3H]diazepam binding, while the maximum response to barbiturates remained unchanged. Significant differences in both the potency and maximum enhancement of [3H]diazepam binding by pentobarbital was observed among brain regions. The rank order potency of pentobarbital in different brain regions was: cerebellum greater than cortex greater than hippocampus, while the rank order efficacy of pentobarbital in these brain regions was reversed. The effects of a combination of anesthetic and/or convulsant barbiturates on [3H]diazepam binding suggested that these compounds function as partial agonists while a combination of anesthetic or convulsant barbiturates with phenobarbital suggested that latter compound antagonized the actions of both anesthetic and convulsant barbiturates. The convulsant benzodiazepine Ro-5-3663 and inosine were more potent as inhibitors of pentobarbital-enhanced than basal (non-pentobarbital enhanced) [3H]diazepam binding. Solubilization of benzodiazepine receptors with Lubrol-PX resulted in a complete loss of barbiturate enhanced [3H]diazepam binding, and greater than a 75% loss in efficacy in the remaining (insoluble receptor) tissue. These data, coupled with recent observations from this and other laboratories, suggests that the site(s) at which barbiturates act to enhance [3H]diazepam binding to benzodiazepine receptors is distinct from the site at which GABA acts to enhance [3H]diazepam binding. The phenomenon of enhanced benzodiazepine binding by barbiturates may be related to the depressant actions of the barbiturates, that is, their direct effects to increase chloride conductance. Although it is premature to assign a pharmacologic correlate to this neurochemical phenomenon, it appears that this action may be related to the anesthetic effects of the barbiturates. However, the definitive assignment of either the electrophysiologic or pharmacologic sequelae to this neurochemical action will require further investigation.

Animals↗
PubMed1982

Nitroimipramines - synthesis and pharmacological effects of potent long-acting inhibitors of [3H] serotonin uptake and [3H] imipramine binding.

A series of nitro derivatives of imipramine have been prepared by nitration of imipramine. Several of the products, especially 2-nitroimipramine (2) and 2,8-dinitro-imipramine (4) were found to be very potent inhibitors of [3H] serotonin uptake and high affinity [3H]imipramine binding in human platelets. In contrast to the parent antidepressant, imipramine, the inhibition of platelet [3H] serotonin uptake and [3H] imipramine binding by the nitro derivatives of imipramine was long-acting and essentially irreversible at low temperatures. These compounds should prove to be valuable tools for subsequent studies on the purification and characterization of the transport protein(s) involved in serotonin uptake and may have novel behavioral and clinical effects.

Binding, Competitive↗
PubMed1982

Blockade of 3-carbomethoxy-beta-carboline induced seizures by diazepam and the benzodiazepine antagonists, Ro 15-1788 and CGS 8216.

The benzodiazepine antagonists Ro 15-1788 and CGS 8216 blocked the clonic and tonic convulsions elicited by 3-carbomethoxy-beta-carboline (beta-CCM). The PD50 values for Ro 15-1788, CGS 8216, and diazepam were: 2.0, 0.6, and 2.0 mg/kg, respectively. Neither Ro 15-1788 nor CGS 8216 potentiated the effect of a threshold convulsant dose of beta-CCM. Moreover, these benzodiazepine antagonists neither attenuated nor potentiated the tremorigenic actions of another beta-carboline, harmaline. Diazepam, however, considerably reduced the tremorigenic actions of this drug.

Animals↗