The hypocholesterolemic effect of phenylethylacetic acid amide in hypercholesterolemic atherosclerotic patients

Rossi, B; Rulli, V

doi:10.1016/0002-8703(57)90215-6

Cited by 14 publications

(1 citation statement)

References 5 publications

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“…The demonstration that 2-phenylbutyramide is a good anticonvulsant corroborates our structure-and mechanism-based hypothesis that α-substituted amide group might represent an antiepileptic pharmacophore acting via inhibition of neuronal nAChRs. Although 2-phenylbutyramide (Hyposterol) has been used clinically in the 1950−1960s as a cholesterol-lowering drug, 35 its antiepileptic activity has not been recognized until now. This suggests that a stronger focus on structure-and mechanism-based approaches will be beneficial in finding new antiepileptic drugs.…”

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confidence: 99%

Anticonvulsants Based on the α-Substituted Amide Group Pharmacophore Bind to and Inhibit Function of Neuronal Nicotinic Acetylcholine Receptors

Krivoshein

2016

ACS Chem. Neurosci.

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Although the antiepileptic properties of α-substituted lactams, acetamides, and cyclic imides have been known for over 60 years, the mechanism by which they act remains unclear. I report here that these compounds bind to the nicotinic acetylcholine receptor (nAChR) and inhibit its function. Using transient kinetic measurements with functionally active, nondesensitized receptors, I have discovered that (i) α-substituted lactams and cyclic imides are noncompetitive inhibitors of heteromeric subtypes (such as α4β2 and α3β4) of neuronal nAChRs and (ii) the binding affinity of these compounds toward the nAChR correlates with their potency in preventing maximal electroshock (MES)-induced convulsions in mice. Based on the hypothesis that α-substituted amide group is the essential pharmacophore of these drugs, I found and tested a simple compound, 2-phenylbutyramide. This compound indeed inhibits nAChR and shows good anticonvulsant activity in mice. Molecular docking simulations suggest that α-substituted lactams, acetamides, and cyclic imides bind to the same sites on the extracellular domain of the receptor. These new findings indicate that inhibition of brain nAChRs may play an important role in the action of these antiepileptic drugs, a role that has not been previously recognized.

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Section: = +mentioning

confidence: 99%

Anticonvulsants Based on the α-Substituted Amide Group Pharmacophore Bind to and Inhibit Function of Neuronal Nicotinic Acetylcholine Receptors

Krivoshein

2016

ACS Chem. Neurosci.

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Solubility of Cholesterol and Gallstones in Metabolic Material

Johnston¹,

Nakayama²

1957

Arch Surg

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Zur Biologie der Fette XI: Über Lipide aus normalen und pathologischen menschlichen Blutseren und xanthomatösem Gewebsmaterial II. Pathologische Lipide und Diskussion

Kaufmann

Schmidt

1960

Fette, Seifen, Anstrichm.

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Die Lipide der Seren gesunder und an Hyperlipidämie, Hypercholesterinämie und Arteriosklerose kranker Versuchspersonen wurden analysiert. Im Fall einer Hypercholesterinämie gelangten auch die Lipide eines Xanthoms zur Untersuchung. Bei den genannten Krankheiten konnten charakteristische Lipidveränderungen festgestellt werden. Hierbei wurde eine bisher unbekannte Lipidfraktion gefunden, die wahrscheinlich zu den Steroiden gehört und die besonders in den pathologischen Seren vermehrt auftrat. Sie machte verestert den Hauptteil der Xanthomlipide aus.

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The hypocholesterolemic effect of phenylethylacetic acid amide in hypercholesterolemic atherosclerotic patients

Cited by 14 publications

References 5 publications

Anticonvulsants Based on the α-Substituted Amide Group Pharmacophore Bind to and Inhibit Function of Neuronal Nicotinic Acetylcholine Receptors

Anticonvulsants Based on the α-Substituted Amide Group Pharmacophore Bind to and Inhibit Function of Neuronal Nicotinic Acetylcholine Receptors

Solubility of Cholesterol and Gallstones in Metabolic Material

Zur Biologie der Fette XI: Über Lipide aus normalen und pathologischen menschlichen Blutseren und xanthomatösem Gewebsmaterial II. Pathologische Lipide und Diskussion

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