Frieda Ungar

Non-enzymic reactions of indoles with pyridine coenzymes and related structures☆

Abstract Certain compounds with “onium”-bearing structures, including diphosphopyridine nucleotide, interact non-enzymically with various indoles, including serotonin and tyrptophan. The products of these interactions are most probably of the charge-transfer complex type. The dependence of these associations on various other groupings present in the interacting species have been studied. Such groupings include the ethylamine residue present in serotonin, the 6-aminopurine moiety of diphosphopyridine nucleotide and the phosphate and pyrophosphate radicals present in the pyridine co-enzymes. An insight into the mechanism of these interactions on the molecular level might be gained by studies of the influence of the composition of the medium (methanol-water, etc.) on the optical properties of N-methylnicotinamide iodide-tryptamine mixtures.

NON-ENZYMATIC INTERACTIONS OF REDUCED COENZYME I WITH INORGANIC PHOSPHATE AND CERTAIN OTHER ANIONS.

WE previously reported1 changes of the absorption spectrum of nicotinamide adenine dinucleotide (coenzyme I, abbreviated NAD+) in solutions containing orthophosphate. In an extension of those investigations2, it has been observed that dihydronicotinamide-adenine dinucleotide (reduced coenzyme I, abbreviated NADH) also reacts with orthophosphate, but in an entirely different manner. Similar changes were observed with dihydronicotinamide adenine dinucleotide phosphate (reduced coenzyme II, abbreviated NADPH) and certain other NADH-analogues. This is a preliminary report of our findings3.

Inhibition of binding of aldehydes of biogenic amines in tissues

Abstract The binding of aldehydes derived from the biogenic amines (i.e. serotonin, dopamine, tryptamine, etc.) is dependent on the substituents attached to the carbonyl residue, as well as the aldehydic group per se . The hydroxyl group on the aromatic nucleus of “biogenic” aldehydes contributes significantly to the attachment of the moieties to brain tissue. Thus, 5-hydroxyindole and catechol were found to compete selectively with the “biogenic” aldehydes for tissue binding sites. The attachment of the “biogenic” aldehydes to tissue may also be prevented in vitro by various reducing or trapping agents, such as ascorbate, cysteine or glutathione. The possible physiologic significance of aldehyde binding to cellular components is discussed.

Receptors: Localization and Specificity of Binding of Serotonin in the Central Nervous System

Formation of a Schiff base between the ethylamine residue of serotonin and an appropriate carbonyl residue at the receptor site may be among the forces holding serotonin onto the receptor. Reduction of this imine may provide a means of permanently labeling receptors as a preliminary to their isolation.

Effect of reserpine on the incorporation in vivo of radioactivity from labeled serotonin and other 5-hydroxy-indole derivatives in mouse brain.

Abstract After endocranial-intraventricular administration of labeled serotonin or 5-hydroxy-indole-3-acetaldehyde into mice, radioactivity is incorporated into acid-insoluble material obtained from the brains of the animals. Under proper experimental conditions pretreatment with pargyline diminishes the incorporation from serotonin, but incorporation from the aldehyde level remains unaffected. Radioactivity due to acid-soluble metabolites obtained from the brain is higher after endocranial injection of serotonin into pargyline pretreated animals as compared to untreated controls. This effect is not observed after administration of the corresponding aldehyde. Pretreatment with reserpine greatly increases the radioactivity due to soluble metabolites in the acid washings and of the incorporation both at the serotonin and the aldehyde levels (endocranial administration). This effect may be observed over a wide range of dosages. In reserpine-pretreated animals, increased radioactivity in the washings is also observed after endocranial injection of a variety of other labeled compounds, including tryptamine, dl -norepinephrine, dopamine, l -lysine and 5-hydroxy-indole-3-acetic acid. The possible mechanism of this effect is discussed.

Effect of monoamine oxidase inhibitors on the labeling of subcellular fractions of brain and liver by 14C-serotonin☆

Abstract We recently observed that under certain conditions, radioactivity from labeled serotonin becomes firmly associated with acid-insoluble material obtained from mitochondrial preparations. This association is prevented by MAO-inhibitors 3 ( Alivisatos et al , 1966a ). A preliminary report of our observations on the mechanism and the potential significance of such associations is presented here.

Drug antagonism and reversibility of the binding of indoleamines in brain

The specificity of the binding of serotonin to brain preparations was investigated with various competitive agents. A probable relationship between their structure and their capability of displacement was suggested. Bufotenine and morphine displaced serotonin (0.5 X 10(-5) M) binding to synaptic membranes 87 and 49% respectively. Dissociation constants of the binding of 5-HT and tryptamine to synaptic membranes, and displacement constants of certain drugs were determined. The binding of 5-HT and tryptamine to calf brain preparations was also investigated by equilibrium dialysis, in order to determine affinity constants and reversibility of the binding. Differences were noted in the specificity of binding sites for serotonin and tryptamine, suggesting a different binding site for tryptamine. Extrapolations of Scatchard plots were used for determination of the constants. A characteristic low dissociation constant was found for 5-HT in synaptic membranes (K approximately X 10(-6) M). Probably, the binding macromolecule (receptor?) is a proteolipid.

Addiction to Barbiturates and Ethanol: Possible Biochemical Mechanisms

The possible interaction between ethanol and the metabolism of biogenic amines in brain tissue has long been an area of concerted research. However, only recently have viable theories emerged which may lead to an understanding of the particular biochemical interaction that might be responsible for the development of a state of addiction to ethanol. Such theories have been nurtured by a recognition of a common pathway of catabolism for the deaminated derivatives of the biogenic amines and acetaldehyde, the initial metabolite of ethanol.