Nicotinamide is a brain constituent with benzodiazepine-like actions

Möhler, Hanns; Polc, P.; Cumin, R.; Pieri, L.; Kettler, R.

doi:10.1038/278563a0

Cited by 184 publications

(49 citation statements)

References 18 publications

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“…We have been able to show a chlordiazepoxide-induced increase in social interaction upon acute administration. The present results showed that nicotinamide but not inosine increased social interaction in a manner comparable to that of chlordiazepoxide and consistent with its activity in a conflict model of anxiety (Mohler et al, 1979 (Gerber & Deroo, 1970), suggests that nicotinamide is unlikely to be an endogenous ligand for the benzodiazepine binding site. But further studies are required to determine the mechanism responsible for the possible anxiolytic action of this compound.…”

Section: Discussionsupporting

confidence: 56%

“…Nicotinamide and inosine are endogenous brain constituents, which have, in the past, been proposed as putative ligands at the benzodiazepine receptor (Mohler et al, 1979;Skolnick et al, 1979). Previous reports by other workers have suggested that both substances have benzodiazepinelike actions.…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, inosine, like benzodiazepines, antagonizes caffeine-induced seizures . In a conflict test nicotinamide restored punishment-suppressed behaviour in rats, an action characteristic of clinically effective anti-anxiety agents (Mohler et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

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Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors

Bold

Gardner²,

Walker

1985

British J Pharmacology

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1The actions of nicotinamide and inosine were investigated on rat cerebellar Purkinje cells using ionophoretic and extracellular recording techniques. 2 lonophoretic application of nicotinamide or inosine showed that they were potent inhibitors of Purkinje cell firing. This inhibition differed from that induced by benzodiazepines in that it was not reversed by the GABA antagonists bicuculline methiodide and picrotoxin. RO 15-1788

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

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Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors

Bold

Gardner²,

Walker

1985

British J Pharmacology

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“…Several substances or fractions have been proposed as endogenous benzodiazepine receptor ligands, including hypoxanthine and inosine (20)(21)(22), nicotinamide (21), a 15,000 Mr heat-stable protein [GABA-modulin (23)], a high Mr (70,000) protein (24), and unidentified fractions (25). All these proposed "ligands" are very weak inhibitors of…”

mentioning

confidence: 99%

“…After evaporation the brown-orange waxy residue was dissolved in 3 ml of 50% ethanol and chromatographed on a Sephadex LH-20 column [1.5 X 84 cm, elution volume (Ve) = 144 ml] in 50% ethanol. The active fraction (y-fraction) was eluted in a volume of [15][16][17][18][19][20][21][22][23][24][25] …”

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confidence: 99%

Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors.

Bræstrup¹,

Nielsen²,

Olsen³

1980

Proc. Natl. Acad. Sci. U.S.A.

472

169

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Benzodiazepines probably exert their anxiolytic, hypnotic, and anticonvulsant effects by interacting with brain-specific high-affinity benzodiazepine receptors. In searching for possible endogenous ligands for these receptors, we have purified a compound 107-fold from human urine by extractions, treatment with hot ethanol, and column chromatography. The compound was identified as ,-carboline-3-carboxylic acid ethyl ester (IIc) by mass spectrometry, NMR spectrometry, and synthesis; HIc was also isolated from brain tissues (20 ng/g) by similar procedures. Very small concentrations of TIc displaced [3H]diazepam completely from specific cerebral receptors, but not from liver andkidney binding sites; the concentration causing 50% inhibition of specific [3H]diazepam binding (IC50) was 4-7 nM compared to ca. 5 nM for the potent benzodiazepine lorazepam. Specific binding sites for quinuclidinyl benzilate, naloxone, spiroperidol, serotonin, muscimol, and WB 4101 were not affected by IIc. In contrast to benzodiazepines, I1c exhibits "mixed type" competitive inhibition of forebrain benzodiazepine receptors (negative cooperativity). We surmise that an endogenous ligand for benzodiazepine receptors may be a derivative of P-carboline-3-carboxylic acid.[3H]Diazepam and [3H]flunitrazepam bind specifically and with high affinity to brain membranes from all higher vertebrates, including man (1-5). Binding is brain specific (6), correlated to pharmacological potency (1, 7-10), located on neurons (11-17), distributed unevenly in the brain (6), and slightly sensitive to seizures and stressful conditions (18,19 5.5. Further impurities were removed by washing twice with 0.05 vol of borate buffer (100 mM, pH 9) and three times with 0.05 vol of aqueous NH3 (100 mM). All aqueous phases were washed twice in counter current fashion with ethyl acetate to decrease losses. The combined ethyl acetate phase was evaporated to dryness and the residue was dissolved in 300 ml of 0.18-0.25 M HCI and washed with 500 ml of diethyl ether, which removed large amounts of impurities. The active fraction was then extracted twice with 500 ml of diethyl ether at pH 5-5.5. After evaporation the brown-orange waxy residue was dissolved in 3 ml of 50% ethanol and chromatographed on a Sephadex LH-20 column [1.5 X 84 cm, elution volume (Ve) = 144 ml] in 50% ethanol. The active fraction (y-fraction) was eluted in a volume of [15][16][17][18][19][20][21][22][23][24][25]

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Neurotransmitters in Anxiety

Hoehn‐Saric¹

1982

Arch Gen Psychiatry

140

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Nicotinamide is a brain constituent with benzodiazepine-like actions

Cited by 184 publications

References 18 publications

Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors

Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors

Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors.

Neurotransmitters in Anxiety

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