Biologically stable analogues of trh with increased neuropharmacological potency

Brewster, David; Dettmar, Peter W.; Metcalf, G.

doi:10.1016/0028-3908(81)90184-2

Cited by 52 publications

(9 citation statements)

References 28 publications

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“…Our results with TRH were in good agreement with the reports described by others (Yarbrough 1979;Brewster et al 1981 ;Miyamoto et al 1981 ;Metcalf 1982). Anti-reserpine activity of YM-14673 was about 8-20 times more potent than TRH, judging from their ED values (Table 1) Time (min) Fig.…”

Section: Oi~ollsupporting

confidence: 82%

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Antagonizing effects of YM-14673, a new TRH derivative, on behavioral and electroencephalographic changes in reserpinized animals

Yamamoto¹,

Shimizu²,

Iwai³

1988

Psychopharmacology

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Effects of YM-14673 (N alpha-[[S)-4-oxo-2-azetidinyl)-carbonyl]-L-histidyl-L-prolinamide dihydrate), a new TRH derivative, on reserpine-induced behavioural and electroencephalographic changes were observed in comparison with those of TRH. YM-14673 antagonized reserpine-induced hypothermia and decrease in convulsion threshold in mice. The number of PGO waves recorded from the lateral geniculate body was decreased by administration of YM-14673 in reserpinized cats. The anti-reserpine activity of intravenous YM-14673 was about 8-20 times more potent than that of TRH. In inhibiting reserpine-induced hypothermia, the oral ED2 degrees C relative to IV ED2 degrees C as an indirect indication of absorption rate of the drugs was 15 for both YM-14673 and TRH. These results suggest that YM-14673 possesses more potent facilitatory effects on the central monoamine systems than TRH.

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Section: Oi~ollsupporting

confidence: 82%

“…Thyrotropin-releasing hormone (TRH) is well known to possess analeptic actions such as shortening effects on pentobarbitone-induced sleeping time and hypothermia in mice (Breese et al 1974;Cott et al 1976;Brewster et al 1981;Metcalf 1982). Interestingly, conscious disturbance in concussed mice (Manaka and Sano 1977;Miyamoto etal.…”

mentioning

confidence: 99%

Antagonizing effects of YM-14673, a new TRH derivative, on behavioral and electroencephalographic changes in reserpinized animals

Yamamoto¹,

Shimizu²,

Iwai³

1988

Psychopharmacology

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“…( Table 2). The central nervous activity of the T R H analogues is also enhanced (Brewster et al 1981;Brewster 1983), possibly as the result of increased brain penetration although an enhanced central potency should also be considered.…”

Section: Improving Passive Permeation Of the Bbbmentioning

confidence: 99%

The Blood-brain Barrier: Principles for Targeting Peptides and Drugs to the Central Nervous System

Begley

1996

Journal of Pharmacy and Pharmacology

272

154

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The presence of the blood-brain barrier (BBB), reduces the brain uptake of many drugs, peptides and other solutes from blood. Strategies for increasing the uptake of drugs and peptide-based drugs include; structural modifications to increase plasma half-life; improving passive penetration of the BBB by increasing the lipophilicity of the molecule; designing drugs which react with transporters present in the BBB; and reducing turnover and efflux from the central nervous system (CNS).

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“…However, TRH has a number of properties inconvenient for the treatment of DAT such as the short duration of action (14), very weak effect on the central nervous system by oral administration (15), and inevitable hormonal effects (16). Therefore, the development of orally administrable TRH analogs having a long action time and weak hormonal effects has been attempted (17,18). TA-0910, [1-methyl-(S)-4,5-dihydroorotyl-L-histidyl-L-prolinamide], is a TRH analog that fulfills these conditions.…”

mentioning

confidence: 99%

Pharmacological study of TA-0910, a new thyrotropin-releasing hormone(TRH) analog. (IV). Effects on experimental memory impairment in mice and rats.

Yamamura¹,

Kawakami²,

Nakagawa³

et al. 1991

Jpn.J.Pharmacol

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ABSTRACT-The effects of a new TRH analog, TA-0910, orally administered, on experimental memory impairments for the one-trial passive avoidance response in anoxic mice (light-dark box), active avoidance response in basal forebrain (BF)-lesioned rats (shuttle box), and delayed alternation task in scopolamine-treated rats (T-maze) were studied. In mice, TA-0910 (3 -30 mg) administered 60 min before the retention trial dose-dependently prolonged the passive avoidance response latency reduced by C02-exposure that was given immediately after the acquisition trial, but not when it was given 60 min before the acquisition or just after the anoxic treatment. In rats, TA-0910 (0.3-3 mg/kg) administered 40-60 min before the test trial, dose-dependently prevented the reduction in mean avoidance rate caused by BF-lesioning and elevated the scopolamine (0.1 mg/kg, i.p.)-induced reduction in percent correct choice level in the alternation task. TRH (30 -300 mg/kg), on the other hand, produced no improvements in any of the above tests. These results suggest that TA-0910 improves impaired memory by correcting the retrieval process of memory.Thyrotropin-releasing hormone (TRH) is a hypothalamic hormone that stimulates secretion of thyrotropin and prolactin. However, radioimmunoassay has demonstrated that twothirds of the total TRH content of the brain is distributed widely in areas other than the hypothalamus (1). Also, autoradiographic studies have revealed that TRH receptors of the brain are concentrated in the cerebral cortex and the limbic system (2, 3). Based on these findings, TRH is considered to play an important role in the brain in the maintenance of consciousness and emotional or intellectual functions (4). Moreover, Yarbrough and Pomara (5) recommended the use of TRH for the treatment of dementia of the Alzheimer type (DAT) from the functional relationship between TRH and central cholinergic nervous system and the effectiveness of TRH in the treatment of dementia of patients with amyotrophic lateral sclerosis complicated by degeneration of cholinergic nerves, and by Metcalf (6) and Griffiths (7) from the effect of TRH to improve disturbance of consciousness (8) and its antidepressant effect (9, 10).Recently, improvements in mental symptoms (such as disturbances in impressibility, emotional disturbances, reduced ability to think, deduced spontaneity, inertia, and apathy) were reported in patients with Alzheimer's disease (AD) and cerebrovascular dementia after administration of TRH (11,12). Tem-

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Biologically stable analogues of trh with increased neuropharmacological potency

Cited by 52 publications

References 28 publications

Antagonizing effects of YM-14673, a new TRH derivative, on behavioral and electroencephalographic changes in reserpinized animals

Antagonizing effects of YM-14673, a new TRH derivative, on behavioral and electroencephalographic changes in reserpinized animals

The Blood-brain Barrier: Principles for Targeting Peptides and Drugs to the Central Nervous System

Pharmacological study of TA-0910, a new thyrotropin-releasing hormone(TRH) analog. (IV). Effects on experimental memory impairment in mice and rats.

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