Curt C. Porter

Inhibition of dopa decarboxylase by the hydrazino analog of α-methyldopa

Abstract dl -σ-Methyl-α-hydrazino-3,4-dihydroxyphenylpropionic acid (HMD) is a potent inhibitor of DOPA decarboxylase in vitro. In vivo, the hydrazino acid inhibited the accumulation of serotonin in the kidneys of mice given 5-hydroxytryptophan (5HTP); it inhibited the urinary excretion of serotonin by 5-HTP-dosed rats; it decreased the rate of expiration of radioactive CO2 by rats which were dosed with l -1-14C-tyrosine, phenylalanine or α-methyldopa. However, it did not affect the rate of expiration of 14C-O2 by rats which were dosed with dl -l-14C-glutamic acid. HMD was concentrated by the kidneys in rats, but did not enter the brain to a measurable extent, and did not affect concentrations of endogenous serotonin in brain. It was itself decarboxylated in the rat to a greater extent after oral than after intraperitoneal administration. HMD apparently did not inhibit monoamine oxidase in vivo.

The effect of TRH and a related tripeptide, L-N-(2-oxopiperidin-6-YL-carbonnyl)-L-histidyl-L-thiazolidine-4-carboxamide (MK-771, OHT), on the depressant action of barbiturates and alcohol in mice and rats

Abstract TRH and a related tripeptide, L-N(2-oxopiperidin-6-ylcarbonyl)-L-histidyl-L-thiazolidine-4-carboxamide (MK-771, OHT), shortened pentobarbital sleeping time of mice in a dose-related fashion. The regression lines were not parallel, so that a strict potency comparison cannot be made between the two compounds. However, comparison between the doses of TRH and OHT required to achieve a maximum response showed the latter to be some 100 times as potent as the former. TRH and OHT shortened methohexital sleeping time of rats and interfered with pentobarbital-induced and alcohol-induced hypothermia in mice. The depressant effect of alcohol upon electroshock escape, rotorod performance, and achievement of a simple, learned task was partly overcome by TRH and OHT. Although quantitative comparisons were not made in all tests, OHT was consistently the more potent of the two compounds.

(S)-norepinephrine in the tissues of mice and rats given racemic erythro-3, 4-dihydroxyphenylserine (DOPS)☆

Abstract The administration of racemic erythro-3, 4-dihydroxyphenylserine (DOPS) to mice resulted in increased concentrations of chemically determined norepinephrine in the hearts and brains. However, radioactive norepinephrine in the brains, resulting from the administration of [2- 14 C]DOPA, was decreased after the administration of erythro-DOPS. The pressor response to tyramine was attenuated in rats which had received this amino acid. It is concluded that in vivo the βS:αS isomer of DOPS, present in the racemic-erythro mixture, yields unnatural (S)-norepinephrine which replaces part of the natural (R)-norepinephrine in central and peripheral adrenergic tissues.

The effect of the optical isomers of α-Methyl-p-tyrosine upon brain and heart catecholamines in the mouse

Abstract l - α -Methyl- p -tyrosine, an inhibitor of the enzymatic conversion of tyrosine to 3-hydroxytyrosine (DOPA), when injected into mice caused a fall in brain and heart catecholamine concentrations. In the brain, 3,4-dihydroxy-phenethylamine concentrations decreased more rapidly and reached lower levels than did norepinephrine concentrations; norepinephrine was not as readily affected in the heart as in the brain. d - α -Methyl- p -tyrosine, while having no effect on tissue catecholamine concentrations, potentiated not only the l -isomer but also certain catecholamine-depleting agents: e.g. methyldopa, l - α -methyl- m -tyrosine and 6-hydroxydopamine. However, it did not potentiate metaraminol, reserpine, or guanethidine. This activity of the d -isomer is correlated with its ability to promote the accumulation of active compounds in the tissues and is probably related to an effect upon membrane permeability.

Some biochemical and pharmacological actions of α-methylphenylalanine

Abstract The catecholamine-depleting activity and certain pharmacological actions of l - α -methylphenylalanine, a tyrosine hydroxylase inhibitor, were compared in a number of species with those of the related α-methyl amino acids, l - α -methyl- p -tyrosine and dl - α -methyl- m -tyrosine. α-Methylphenylalanine was more active than α -methyl- p -tyrosine in depleting heart norepinephrine, but was less effective in reducing central amines; in addition, its duration of action in the heart was more prolonged. α -Methyl- m -tyrosine proved to be the most active compound on both brain and heart catecholamines. Metaraminol was found to be a metabolite of α-methylphenylalanine and was identified in the hearts, brains and adrenals of mice, rats and dogs. No overt signs of sedation were seen in dogs or squirrel monkeys given α-methylphenylalanine, although loss of avoidance responding could be demonstrated. This contrasted with results obtained with α -methyl- m -tyrosine, which produces stimulation and an increase in lever-pressing behavior. α-Methylphenylalanine, as found with α -methyl- p -tyrosine and α -methyl- m -tyrosine, reduced cardiac responses to the indirect sympathomimetic amines and to adrenergic nerve stimulation. It was concluded that the pattern of biochemical and pharmacologie events after α-methylphenylalanine falls between those because of α -methyl- p -tyrosine, a relatively pure tyrosine hydroxylase inhibitor, and α -methyl- m -tyrosine, whose effects are related predominantly to its rapid metabolism to metaraminol with a consequent release and depletion of catecholamines.

Displacement of norepinephrine from the rat heart by 14C-metaraminol

Abstract Rats were injected with submaximal quantities (0.24 mg/kg) of 14 C-metaraminol, i.e. enough to lower the concentration of norepinephrine in the heart by about 60 per cent, measured 18 hr after drug administration. In the ventricles at 18,42 and 66 hr after metaraminol injection and in the atria at the two latter times, radioactivity was present in amounts sufficient to account exactly for the norepinephrine missing, on a mole-for-mole displacement basis. Atrial radioactivity 18 hr after metaraminol administration was insufficient to account for the whole of the missing catecholamine. Possibly at 18 hr a steady state had not been reached in the atria, an interpretation which is strengthened by the fact that other catecholamines (epinephrine and dopamine) were present only in trace amounts. Chemically determined metaraminol was consistently less than indicated by radiocounting. Even though no evidence was gained for the presence of 14 C-α-methylnorepinephrine in the tissue, it is possible that metabolites of metaraminol account for part of the norepinephrine displacement observed. The administration of larger amounts of 14 C-metaraminol (3 mg/kg) resulted in catecholamine depletion greater than that accounted for by radio-activity in the tissue, and this was particularly striking in the atria. Thus, the relationship between tissue radio-activity and norepinephrine concentration depends upon several factors, and only under certain conditions, as described above, is a one-for-one displacement of the catecholamine clearly demonstrated.

4, 4, 6-Trimethyl-3, 4-dihydropyrimidine-2-thiol, an effective inhibitor of dopamine-β-hydroxylation in vivo

Abstract 4, 4, 6-Trimethyl-3, 4-dihydropyrimidine-2-thiol, although considerably less potent (1/500) than disulfiram as an inhibitor of dopamine-β-hydroxylation in vitro , is 10–20 times as potent as disulfiram, both administered intraperitoneally, in vivo . The pyrimidinethiol decreases the concentration of norepinephrine in the brain (mice and rats) but does not decrease the concentration of dopamine in that organ; it inhibits the depleting action of methyldopa and α- methyl -m- tyrosine on brain and heart norepinephrine, and of α- methyl -m- tyramine and α-methyl-dopamine on heart norepinephrine, and its effects upon tissue catecholamines are additive to those of DOPA and of a monoamine oxidase inhibitor; it inhibits restoration of the tyramine-pressor response in reserpine-treated rats by α-methyldopamine. The pyrimidinethiol is perhaps twice as potent as disulfiram as an inhibitor of alcohol metabolism in the rat, and in this function it, like disulfiram, acts at the aldehyde dehydrogenase step of oxidation. The pyrimidinethiol, like other thiourea derivatives, blocks the uptake of iodine by the rat thyroid gland in vivo . In this function it is about 1/150 as potent as propylthiouracil and six times as potent as disulfiram. The pyrimidinethiol is well absorbed after oral administration; for this reason, and because of its potency advantage over disulfiram, the compound should be superior to dilsulfiram in a number of situations.

Liver alcohol dehydrogenase inhibition by fatty acid amides, N-alkylformamides and monoalkylureas

Abstract With ethanol as substrate, N-n-alkylformamides and mono-n-alkylureas, like fatty acid amides, inhibited horse liver alcohol dehydrogenase uncompetitively, presumably by forming ternary complexes with the enzyme - reduced nicotinamide adeninedinucleotide binary complex. Compounds with 11- or 12-atom chains were better inhibitors than longer or shorter chain compounds. In vivo (mice), the urea derivatives were ineffective, as were the amides, with the exception of butanamide; the latter compound was less active than iso-butanamide. Formamides with 4- to 12-atom chains were active in vivo but, unlike in vitro , the shorter chain compounds were the most potent. A variety of branched-chain alkyl-, cyclic alkyl- and arylalkylamides and N-substituted formamides also inhibited alcohol dehyrogenase in vitro .

New Metabolizable Immunologic Adjuvant for Human Use. 6. Disposition of Radioactivity after Administration of Labelled Vaccine To the Rat

Summary Three batches of Adjuvant 65 were prepared, each labelled with C14 in one of the components, and emulsified with aqueous suspensions of killed influenza virus. The resulting vaccines were administered intramuscularly to rats, and the disposition of the tracer was followed for 120 days. The C14 from aluminum monostearate-1-C14 and from Arlacel A (mannide-l-C14-monooleate) disappeared from the injection site more rapidly than C14 from peanut oil (oil containing a small excess of glyceryltrioleate added as carboxyl C14-labelled triglyceride). Expiration of C14O2 by the rats which were injected with labelled aluminum stearate or labelled peanut oil vaccines demonstrates that these fatty materials reached the metabolic pools and were metabolized normally. Radioactivity injected with the vaccine as mannide-labelled Arlacel A did not accumulate in the tissues, most of it being excreted via the urine. It is concluded that the fatty components of the Adjuvant 65 vaccines were absorbed after intramuscular administration and were disposed of via normal metabolic routes.

Some biochemical and pharmacological actions of (—) erythro-meta-(meta-chlorobenzyloxy) -2-(1-aminoethyl)-benzyl alcohol: A derivative of metaraminol☆

Abstract (—)Erythro-meta-(meta-chlorobenzyloxy)-2-(1-arninoethyl)-benzyl alcohol, a meta-chlorobenzyl ether of metaraminol, administered to mice, rats and dogs, causes depletion of peripheral stores of norepinephrine and their partial replacement with metaraminol. Consequently, the ether depresses adrenergic nerve transmission in dogs and lowers blood pressure in renal hypertensive rats. However, acute presser responses are either minimal (rats) or absent (dogs) following administration of the ether, due to the slow formation of metaraminol. Unlike α -methyl- m -tyrosine, the chlorobenzyl ether of metaraminol does not produce central nervous system effects. In the brain the amino acid is converted to metaraminol, while metaraminol as derived from the ether is absent or appears only in low concentration.