Synthetic thyrotropin-releasing factor analogs. 3. Effect of replacement or modification of histidine residue on biological activity

Rivier, Jean; Vale, Wylie; Monahan, Michael W.; Ling, N; Burgus, Roger

doi:10.1021/jm00275a010

Cited by 63 publications

(24 citation statements)

References 4 publications

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“…The TRH anaolog, 3Me-H TRH (pGlu-3-His-Pro-NH 2 ), is ten times more biologically active than TRH due to its greater binding affinity for the TRH receptor [57,59]. Additionally, 3Me-H TRH is more metabolically stable than TRH as the addition of the 3Me substitution renders the tri-peptide more resistant to enzymatic degredation [20].…”

Section: Introductionmentioning

confidence: 99%

An analog of thyrotropin-releasing hormone (TRH) is neuroprotective against glutamate-induced toxicity in fetal rat hippocampal neurons in vitro

et al. 2007

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TRH has been found to be efficacious in treating certain neurodegenerative disorders such as epilepsy, Alzheimer's disease, neurotrauma and depression, however, its mechanism of action is poorly understood. Since Glutamate (Glu) toxicity has been implicated in these disorders, we utilized primary enriched cultures of rat fetal (E 17) hippocampal neurons to test the hypothesis that an analog of TRH, 3-Methyl-Histidine TRH (3Me-H TRH), given concurrently with Glu would protect such neurons against cell damage and cell death. Cell viability was assessed via Trypan Blue exclusion cell counts and neuronal damage was determined by assaying lactic acid dehydrogenase (LDH) released in the conditioned media. Fetal hippocampal neurons were cultured in neurobasal media for 7 days. On day 7, neurons (10 6 /well) were treated with: control media, 10 μM 3Me-H TRH, 500 μM Glu, or 500 μM Glu with either 10, 1, 0.1, 0.01 or 0.001 μM 3Me-H TRH. Both media and neurons were harvested 16 hr after treatment. Prolonged exposure to 10 μM 3Me-H TRH was not toxic to the cells, whereas, neurons exposed to 500 μM Glu resulted in maximal cell death. Notably, 10, 1 and 0.1 μM 3Me-H TRH, when co-treated with 500 μM Glu protected fetal neurons against cell death in a concentration-dependent manner. These results provide support for an important neuroprotective effect of TRH/analogs against glutamate toxicity in primary hippocampal neuronal culture, and implicate a potentially beneficial role of TRH/analogs in neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

An analog of thyrotropin-releasing hormone (TRH) is neuroprotective against glutamate-induced toxicity in fetal rat hippocampal neurons in vitro

et al. 2007

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“…Previous studies have shown that modification of the imddazole ring of histidine has profound effects on the biological activity of TRH. The N-methylated analog, 3-Me-Im-TRH, is about ten times as active as TRH in assays for TSH release while the l-me2hyl analog is inactive (14). Replacement of 2 histidine by [Pyr(l)Ala ) also gives an active analog while [Pyr(3)Ala] is only weakly active (15).…”

Section: Introduci'ionmentioning

confidence: 99%

Effect of thyrotropin releasing hormone and some of its histidine analogs on the cardiovascular system and prolactin release in the conscious rat

et al. 1986

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The cardiovascular and endocrine activity of three analogs of thyrotropin releasing hor.mone (TRH), 4-nitro-imidazole TRH (4-nitro-TRH), 2-trifluoro-methyl-imidazole TRH (2-TFM-TRH) and 4-trifluoromethyl-imidazole TRH (4-TFM-TRH), was compared to TRH in conscious rats. Injection of TRH or the three analogs (1 mg/kg or 5 mg/kg) into the arterial line induced increases in mean arterial pressure, pulse pressure and heart rate and raised plasma prolactin (PRL). None of the analogs were more potent than TRH in inducing cardiovascular changes. The 4-TFM-TRH was significantly less potent than the 2-TFM-TRH in increasing blood pressure, while the nitro-TRH was more potent than the 2-TFM-TRH in producing tachycardia. TRH induced a two-fold increase in PRL at the 5 mg/kg dose, while both the fluorinated analogs elici ted a 4 to 5 fold increase in PRL at the higher dose. The present results suggest that the receptors for TRH-elicited PRL release differ from TRH-receptors involved in its cardiovascular actions. INTRODUCI'IONIn addition to the thyrotropin release, thyrotropin releasing hor.mone (TRH) releases prolactin (PRL) from the pituitaLY of several mammalian species (1). Moreover, TRH has central nervous system actions which are totally unrelated to its effect on the hypothalamopituitary axis (2,3). In both experimental animals (4-7) and humans (8,9), TRH producespresser and tachycardic responses. The variety of autonomic endocrine and neural functions regulated by TRH suggests that different receptors might mediate the various effects of TRH. The existance of multiple TRH receptors is supported by both biological (10,11) and biochemdcal studies (3,12,13). Appropriate modification of the TRH molecule might, therefore, yield analogs with an action selective for either neuroendocrine or central nervaus system. 63

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“…The (des)-LRF peptides show less than 0.1% LRF activity with the exception of (des10)-LRF with a potency of approximately 10% LRF. Neither (limMe-His2)-LRF nor (3""Mc-His2)-LRF have increased LRF activity in contradistinction to the increased activity of (3"nMe-His2)-TRF which is 10 times more potent than TRF (pGlu-His-Pro-NH.,) [12]. Des-His2-LRF had no statistically significant LRF activity at the doses tested.…”

Section: Biological Resultsmentioning

confidence: 84%

“…The method used in this laboratory starting with the benzhydrylamine resin described by Pietta and Marshall [9] has been previously described in Monahan et al [10,11] and R ivier et at. [12], It can be summarized as follows: The C-terminal residue is coupled to 111 via dicyclohexyl-carbodiimide (DCC) by standard solid-phase techniques as are succeeding residues. The i.-amino acids are coupled as the N-t-butoxycarbonyl (BOC)-protected derivatives.…”

Section: Methods Of Peptide Synthesesmentioning

confidence: 99%

Polypeptides Antagonists of the Hypothalamic Luteinizing Hormone Releasing Factor

Guillemin¹,

Amoss²,

Blackwell³

et al. 1971

Gynecol Obstet Invest

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Techniques are described for the solid-phase synthesis of the decapeptide luteinizing hormone releasing factor (LRF) and for the testing of its biological activity in vitro (dispersed cells of rat pituitary gland in monolayer cultures). The biological activity of several (LH)LRF analogues is reported. Two analogues of the hypothalamic Luteinizing hormone releasingthalamic modified factor at the histidine-2 position were tested for biological activity (secretion of luteinizing hormone) in cultures of dis- persed rat anterior pituitary cells. The analogue in which glycine was substituted for histidine at position-2 [Gly²] LRF behaves as a partial agonist releasing less than 50 % of the luteinizing hormone secreted at maximum concentrations of the releasing factor, while the analogue in which histidine at position-2 is deleted has no significant agonist activity at any of the doses tested. When added to the cultured cells at molar ratios 103 to 101 times that of the luteinizing hormone releasing factor, both analogues decrease the amount of luteinizing hormone secreted in response to the releasing factor.

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Synthetic thyrotropin-releasing factor analogs. 3. Effect of replacement or modification of histidine residue on biological activity

Cited by 63 publications

References 4 publications

An analog of thyrotropin-releasing hormone (TRH) is neuroprotective against glutamate-induced toxicity in fetal rat hippocampal neurons in vitro

An analog of thyrotropin-releasing hormone (TRH) is neuroprotective against glutamate-induced toxicity in fetal rat hippocampal neurons in vitro

Effect of thyrotropin releasing hormone and some of its histidine analogs on the cardiovascular system and prolactin release in the conscious rat

Polypeptides Antagonists of the Hypothalamic Luteinizing Hormone Releasing Factor

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