Effects of a new TRH analogue, YM-14673 on the central nervous system

SummaryThe effects of a new TRH analogue, YM-14673 (Nα-[{(S)-4-oxo-2-azetidinyl}carbonyl]-L-histidyl-L-prolinamide dihydrate) on the central nervous system were compared with those of TRH. YM-14673 was 10–40 times more potent than TRH in antagonizing pentobarbital-induced sleep and hypothermia, and ethanol-induced hypothermia in mice. YM-14673 accelerated recovery from disturbed consciousness induced by concussive head trauma in mice and normalized the behavior and spontaneous EEG disturbed by electrolytic lesion of the hypothalamus in cats with 25 -100 times greater potency than that of TRH. In the tests on pentobarbital sleeping time and EEG disturbance, the cerebral activating activity of YM-14673 was 8 –36 times longer-lasting than that of TRH. These results indicate that YM-14673 possesses potent arousal effects on the central nervous system. The mode of action of YM-14673 was also discussed.

[1]  S. W. Ranson,et al.  CATALEPSY CAUSED BY LESIONS BETWEEN THE MAMMILLARY BODIES AND THIRD NERVE IN THE CAT , 1932 .

[2]  G. Yarbrough.  On the neuropharmacology of thyrotropin releasing hormone (TRH) , 1979, Progress in Neurobiology.

[3]  G. Breese,et al.  Effects of thyrotropin-releasing hormone in depression. , 1972, Lancet.

[4]  Ray S. Snider,et al.  A stereotaxic atlas of the cat brain , 1987 .

[5]  T. Takayanagi,et al.  EFFECT OF THYROTROPIN-RELEASING HORMONE ON ATAXIA OF SPINOCEREBELLAR DEGENERATION , 1980, The Lancet.

[6]  G. Metcalf.  Regulatory peptides as a source of new drugs — the clinical prospects for analogues of TRH which are resistant to metabolic degradation , 1982, Brain Research Reviews.

[7]  K. Inanaga,et al.  Effect of a thyrotropin releasing hormone analog in a patient with myoclonus epilepsy. , 1981, The Kurume medical journal.

[8]  B. Green,et al.  Neuropeptides in spinal cord injury: Comparative experimental models , 1983, Peptides.

[9]  G. Metcalf,et al.  Biologically stable analogues of trh with increased neuropharmacological potency , 1981, Neuropharmacology.

[10]  G. Patrick,et al.  EFFECT OF CONCUSSIVE HEAD INJURY ON CENTRAL CATECHOLAMINE LEVELS AND SYNTHESIS RATES IN RAT BRAIN REGIONS 1 , 1979, Journal of neurochemistry.

[11]  M. Miyamoto,et al.  γ-butyrolactone-γ-carbonyl-histidyl-prolinamide citrate (DN-1417) : A novel TRH analog with potent effects on the central nervous system , 1981 .

[12]  P. Bailey,et al.  TUMORS IN THE REGION OF THE THIRD VENTRICLE: THEIR DIAGNOSIS AND RELATION TO PATHOLOGICAL SLEEP , 1929 .

[13]  M. Gershengorn,et al.  Thyrotropin-Releasing Hormone: Evidence for Thyroid Response to Intravenous Injection in Man , 1972, Science.

[14]  G. Metcalf,et al.  Thyrotropin-releasing hormone (TRH) analogues show enhanced CNS selectivity because of increased biological stability , 1981, Regulatory Peptides.

[15]  B. Cooper,et al.  Investigations into the mechanism of reduction of ethanol sleep by thyrotropin-releasing hormone (TRH). , 1976, The Journal of pharmacology and experimental therapeutics.

[16]  H. Toguchi,et al.  Absorption of thyrotropin-releasing hormone after oral administration of TRH tartrate monohydrate in the rat, dog and human. , 1984, Journal of pharmacobio-dynamics.

[17]  B. Cooper,et al.  202 – INTERACTIONS OF THYROTROPIN RELEASING HORMONE WITH CENTRALLY-ACTING DRUGS , 1977 .

[18]  J. Wilber,et al.  Increased serum prolactin after administration of synthetic thyrotropin releasing hormone (TRH) in man. , 1971, The Journal of clinical endocrinology and metabolism.

[19]  M. Shimizu,et al.  Cerebral activating properties of indeloxazine hydrochloride , 1987, Neuropharmacology.

[20]  L. Marshall,et al.  Vertebrobasilar spasm: a significant cause of neurological deficit in head injury. , 1978, Journal of neurosurgery.

[21]  G. Breese,et al.  Thyrotropin releasing hormone: enhancement of DOPA activity in thyroidectomized rats. , 1974, Life sciences.

[22]  W. Engel,et al.  EFFECT ON WEAKNESS AND SPASTICITY IN AMYOTROPHIC LATERAL SCLEROSIS OF THYROTROPIN-RELEASING HORMONE , 1983, The Lancet.