Identification of harman in the rat arcuate nucleus

Shoemaker, D.W.; Cummins, Joseph T.; Bidder, T. George; Boettger, H. G.; Evans, M.

doi:10.1007/bf00499914

Cited by 60 publications

(11 citation statements)

References 35 publications

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“…Therefore, a ratio of two [3H]harman-labeled sites per one MAO-A holodimer is more likely. Bosin et al (1989) determined a harman concentration of -2.3 nmol/kg in the whole rat brain, but Shoemaker et al (1980) detected 1.3 pmoi/kg in the rat arcuate nucleus. Thus, harman may represent, in some compartments, a significant endogenous MAO-A inhibitor with physiological relevance, as is possibly tribulin for MAO-B (Glover et al, 1988).…”

Section: Discussionmentioning

confidence: 97%

“…Harman ( 1-methyl-/3-carboline; Fig. 1) has been detected in many plants and fungi, as well as being an endogenously occumng biogenic amine in rats and humans (Shoemaker et al, 1980;Airaksinen and Kari, 1 9 8 1~;Rommelspacher and Susilo, 1985;Bosin et al, 1989). Harman belongs to a group of naturally occurring B-carbolines (BCs) with neurotropic effects in rat and humans, e.g., tremor, tonic-clonic convulsions, and hallucinations (Gunn, 1935;Sigg et al, 1964;Naranjo, 1979;Airaksinen and Kari, 1981b).…”

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confidence: 99%

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[³H]Harman Binding Experiments. I: A Reversible and Selective Radioligand for Monoamine Oxidase Subtype A in the CNS of the Rat

May¹,

Rommelspacher²,

Pawlik

1991

Journal of Neurochemistry

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Harman (1-methyl-beta-carboline) is an endogenous compound with neurotropic properties in rats and humans. In a novel in vitro binding assay, the binding site of [3H]harman has been characterized in the rat crude mitochondrial (P2) fraction. The binding was saturable and reversible. Only a single high-affinity binding site was detected by kinetic, saturation, and displacement analyses in the cerebral cortex of the rat. The linear Scatchard plots revealed equilibrium dissociation constant (KD) values of approximately 2.5 nM at 0 degrees C, approximately 9 nM at 23 degrees C, and approximately 30 nM at 37 degrees C. Among six CNS regions (hypothalamus, hippocampus, cerebral cortex, striatum, cerebellum, and spinal cord), the highest density of binding sites (Bmax) was determined in the hypothalamus (approximately 5.5 pmol/mg of protein) and the lowest in the spinal cord (approximately 2.0 pmol/mg of protein). Several drugs known to affect serotonergic, adrenergic, dopaminergic, cholinergic, or GABAergic neurotransmission inhibited specific binding at best in the micromolar range. In contrast, potent and selective inhibitors of monoamine oxidase subtype A were active in the lower and middle nanomolar range. The displacing potency (apparent Ki) of substrates and inhibitors of monoamine oxidase correlated positively and highly significantly with the corresponding values of the inhibition of monoamine oxidase activity of subtype A (r = 0.92, p less than 0.001, n = 17) but not of subtype B (r = -0.47, p greater than 0.05, n = 15). In conclusion, [3H]harman was identified as a specific ligand of the active site of the A subtype of monoamine oxidase in rat brain.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

[³H]Harman Binding Experiments. I: A Reversible and Selective Radioligand for Monoamine Oxidase Subtype A in the CNS of the Rat

May¹,

Rommelspacher²,

Pawlik

1991

Journal of Neurochemistry

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“…As harmane has been identified in both rat brain (Shoemaker et aL, 1980) and human platelets (Bidder et al,, 1979), its MAO inhibitory ability may well have some physiological role; perhaps we would be unwise to ignore it as a possible aetiological agent during studies of abnormal platelet MAO activity . Harmane is also of interest as a possible endogenous benzodiazepine ligand, with an I50 of about 7 x 10 .6 M (Rommelspacher et al, 1980 a).…”

Section: Resultsmentioning

confidence: 97%

“…Rommelspacher et al (1980 b) also reported the presence of the unsaturated carboline, harmane, in the same samples. Harmane has been identified in human platelets (Bidder et al, 1979) and rat arcuate nucleus (Shoemaker et aL, 1980). Perhaps of greater potential interest, Braestrup et al (1980) have reported the isolation of ethyl /?-carboline-3-carboxylic acid, a potent benzodiazepine receptor ligand, from human urine; but, as the authors acknowledge, it seems likely that an unknown precursor became esterified and perhaps further modified chemically, by the extraction procedure.…”

Section: Introductionmentioning

confidence: 96%

?-Carbolines as selective monoamine oxidase inhibitors:In vivo implications

Glover¹,

Liebowitz²,

Armando³

et al. 1982

J. Neural Transmission

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The inhibitory action of a range of beta-carbolines on human and rat monoamine oxidase (MAO) A and B has been studied. Concentrations of 5-hydroxytryptamine and phenylethylamine, approximately at their Km values, were used as substrates for MAO A and B respectively. A wide variation in selectivity was found, with harmaline being 10,000 times more potent an inhibitor of A than B whereas, using tetrahydro-beta-carboline and harmane, the difference was nearer to ten-fold. Of the carbolines which have been found endogenously, tetrahydro-beta-carboline, 6-methoxytetrahydro-beta-carboline and harmane are all sufficiently potent inhibitors of human MAO A, with I50 values of 5 X 10(-6), 10(-6), 5 X 10(-7) M respectively, for this property to be of possible physiological significance. Harmane, with an I50 of 5 X 10(-6) M, might also play a role as an inhibitor of MAO B.

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“…In addition, harmane has also been shown to interact with I-BS with a higher affinity (IC 50 at I 1 -BS=31 nM, K i at I 2 -BS=49 nM) [97] compared to agmatine. The natural occurrence of harmane in the arcuate nucleus [98], a region rich in both I 2 -BS [99] and MAOs [100], could suggest a possible role for harmane as an endogenous ligand at these sites.…”

Section: Harmane -The Endogenous Ligand At Imidazoline Binding Sites?mentioning

confidence: 99%

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

Ghazaleh¹,

Tyacke²,

Hudson³

2015

J Neurol Neurosci

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The imidazoline binding sites (I-BS) represent a heterogenous family of receptors/sites that stemmed from studies investigating the hypotensive effect of the imidazoline compound clonidine [1]. Structure-affinity relationship studies complemented by functional analyses characterised three types of I-BS, denoted I 1 -BS, I 2 -BS (I 2A and I 2B ) and I 3 -BS [2]. Extensive research has established the involvement of central I 1 -BS in cardiovascular function [3]. Other reported functions include alleviating symptoms associated with metabolic syndrome X [4] and Huntington's Disease [5], promoting natriuresis [6], regulating intraocular pressure [7], and modulating mRNA expression for phenylethanolamine N-methyl transferase (PNMT) [8]. Furthermore, the expression of these sites was shown to be altered in conditions such as depression [9] and dysphoric premenstrual syndrome [10] AbstractOver the past few years, a vast amount of research has shed light on the pharmacology of imidazoline binding sites (I-BS). To date, at least three classes of imidazoline binding sites have been characterised in accordance to their localisation, drug selectivity, proposed signalling pathways and functional roles. The existence of these sites raises the question as to whether an endogenous modulator exists. The identification of an endogenous extract denoted as clonidine displacing substance prompted the search for the active ingredient capable of mimicking the action of selective ligands at these sites. A number of candidates have been isolated and their functional activities have been assessed at these sites. Such endogenous ligands include agmatine, imidazoleacetic acid ribotide and the β-carboline harmane. As of yet, no consensus has been made to confirm the identity of the endogenous ligand at I-BS. The current review collates and reports what is known about these substances and their functional significance at I-BS.

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Identification of harman in the rat arcuate nucleus

Cited by 60 publications

References 35 publications

[³H]Harman Binding Experiments. I: A Reversible and Selective Radioligand for Monoamine Oxidase Subtype A in the CNS of the Rat

[³H]Harman Binding Experiments. I: A Reversible and Selective Radioligand for Monoamine Oxidase Subtype A in the CNS of the Rat

?-Carbolines as selective monoamine oxidase inhibitors:In vivo implications

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

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Identification of harman in the rat arcuate nucleus

Cited by 60 publications

References 35 publications

[3H]Harman Binding Experiments. I: A Reversible and Selective Radioligand for Monoamine Oxidase Subtype A in the CNS of the Rat

[3H]Harman Binding Experiments. I: A Reversible and Selective Radioligand for Monoamine Oxidase Subtype A in the CNS of the Rat

?-Carbolines as selective monoamine oxidase inhibitors:In vivo implications

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

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[³H]Harman Binding Experiments. I: A Reversible and Selective Radioligand for Monoamine Oxidase Subtype A in the CNS of the Rat

[³H]Harman Binding Experiments. I: A Reversible and Selective Radioligand for Monoamine Oxidase Subtype A in the CNS of the Rat