Thyrotropin-releasing hormone, synthesis

PG Pietta, PF Cavallo, K Takahashi, GR Marshall. Preparation and use of benzhydrylamine polymers in peptide synthesis. II. Syntheses of thyrotropin releasing hormone, thyrocalcitonin 26-32, and eledoisin. J Org Chem 39, 44, 1974. 

S. Muranishi, A. Sakai, K. Yamada, M. Murakami, K. Tanaka, Y. Kiso, Lipophilic Peptides Synthesis of Lauryol Thyrotropin-Releasing Hormone and Its Biological Activity ,... 

Control of thyroid function via thyroid-pituitary feedback is also discussed in Chapter 37. Briefly, hypothalamic cells secrete thyrotropin-releasing hormone (TRH) (Figure 38-3). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyrotropin (thyroid-stimulating hormoneTSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback fashion in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. 

Synthesis of a r >[C(=S)NH] Tripeptide Analogue of Thyrotropin Releasing Hormone pGlm >[C(=S)-NH]His-Pro-NH2J t22l... 

The thyroid-pituitary-hypothalamus axis controls thyroid hormone homeostasis. Thyrotropin-releasing hormone (TRH), released from the hypothalamus, stimulates the synthesis and release of thyroid-stimulating hormone (thyrotropin, TSH) from the anterior pituitary. TSH increases the release of thyroid hormones by several mechanisms, including stimulation of the I pump. While lower than normal levels of T3 and T4 cause an exaggerated response of the pituitary to TRH, released thyroid hormones, in feedback control, blunt the stimulating action of TRH on the pituitary. For further discussion of TSH and TRH biochemistry, see, for example, the review by Kannan48. 

The polymeric active ester method has been used successfully for the preparation of several small- to medium-sized peptides in very pure form the potentiality of the method has also been illustrated by the synthesis of a number of biologically active protein sequences like bradykinin 106), thyrotropin-releasing hormone 107), ACTH sequences 105), and LH—RH 108> in good overall yields. 

Gillessen D, Felix AM, Lergier W, Studer RO. Synthesis of thyrotropin-releasing hormone (TRH) and related peptides. Helv. Chim. Acta. 1970 53 63-72. 

The pituitary gland is involved in feedback regulation of thyroid activity High levels of T4 in the bloodstream result in inhibition of TSH secretion. Low levels of T4 result in an increase in TSH secretion. These effects are dependent on the conversion of T4 to T3 within the pituitary, fhe activity of the pituitary is controlled by thyrotropin-releasing hormone (TRH), a hormone synthesized in the hypothalamus. TRH is a tripeptide with the structure pyroglutamate-histidine-proline-NH . Note the C-terminal amide group, which is required for the activity of many peptide hormones. TRH stimulates the synthesis and secretion of TSH. Apparently TRH is involved in regulating the sensitivity of the pituitary to the inhibitory feedback control mechanism mentioned earlier. 

Thyroid hormones also accelerate fetal lung maturation. Fetal thyroid hormone levels may be increased by antenatal administration of thyrotropin-releasing hormone (TRH), a tripeptide that crosses the placental barrier, stimulates fetal pituitary production of thyroid stimulating hormone (TSH), and which, in turn, increases fetal thyroid hormone production (Chapter 33). This indirect method of enhancement of fetal thyroid hormone production is utilized because thyroid hormones do not readily cross the placental barrier. Insulin delays surfactant synthesis and so fetal hyperinsulinemia in diabetic mothers may increase the incidence of RDS even in the full-term infant. Androgen synthesized in the fetal testis is the probable cause of a slower onset of surfactant production in male fetuses. Prophylactic, or after onset of RDS, administration of synthetic or natural pulmonary surfactants intratracheally to preterm infants improves oxygenation and decreases pulmonary morbidity. 

Additional diabetes related studies in rats or mice fed copper-deficient diets document impaired synthesis or release of thyroid stimulating hormone in response to thyrotropin-releasing hormone [421 ], atrophy of pancreatic acinar tissue [422, 423, 424] impaired release of pancreatic amylase [413], and increased glycosylated haemoglobin [425]. 

FIGURE 56-5 Regulation of thyroid hormone secretion. Myriad neural inputs influence hypothalamic secretion of thyrotropin-releasing hormone (TRH). TRH stimulates release of thyrotropin (TSH, thyroid-stimulating hormone) from the anterior pituitary TSH stimulates the synthesis and release of the thyroid hormones and T,. and T, feed back to inhibit the synthesis and release of TRH and TSH. Somatostatin (SST) can inhibit TRH action, as can dopamine and high concentrations of glucocorticoids. Low levels of L are required for thyroxine synthesis, but high levels inhibit thyroxine synthesis and release. 

A. Winokur, and K. A. Gary, J. Med. Chem., 38, 2866 (1995). Peptide Mimetics of Thyrotropin-Releasing Hormone Based on a Cyclohexane Framework Design, Synthesis, and Cognition-Enhancing Properties. 

This strategy was successfully applied fo a practical synthesis of a trisaccharide part of globotriaosyl ceramide. A highly fluorinated carboxyUc acid (Hfb) was also prepared and used for rapid and large-scale synthesis of a thyrotropin-releasing hormone (TRH). ... 

S. Bajusz, I. Fauszt, Improved method for the synthesis of the thyrotropin releasing hormone TRH. Acta Chim. Acad. Sci. Hung 75 419-422 (1973)... 

The central focus of thyroid system control is the pituitary thyrotroph cell. Figure 1 summarizes the major events in thyrotroph cell control of thyrotropin (TSH) synthesis and release. Hypothalamic thyrotropin releasing hormone (TRH) binds to its receptor, stimulating the synthesis and release of TSH. Based on available evidence it appears that TRH-receptor Interaction increases intracellular free calcium concentrations both by mobilization from intracellular pools and by increasing transport via cell membrane calcium channels (2). The increased cytoplasmic calcium activates TSH release. Cyclic AMP may play a role both TRH and cAMP seem capable of increasing calcium inflow into the thyrotroph, as well as mobilizing calcium from intracellular pools. However, cAMP does not appear to be the primary mediator of the TRH effect. 

Figure 1. Details of thyrotropin releasing hormone (TRH) and triiodothyronine (T3) regulation of pituitary TSH synthesis and release. See text for details. 5 MD is iodothyronine 5 monodeiodinase, type II.

Synthesis of thyrotropin releasing hormone as well as several oligopeptides in an inhomogeneous two polymer system... 

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