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Abstract
Diazomethylketone and Chloromethylketone analogs of thyrotropin releasing hormone have been synthesized and studied for their inhibitory effect on TRH-induced TSH and PRL release in the Long Evans rat by in vitro and in vivo techniques. TRH Diazomethylketone and TRH Chloromethylketone represent the first potent antagonist of TRH-induced TSH and PRL release whereby the natural amino acid sequence, pyroglutamylhistidylproline, has been preserved. The structural similarity of these compounds to thyrotropin releasing hormone implies that these compounds are competitive antagonist. It is not obvious that other inhibitors of TRH releasing activity such as cyclopentanecarbonylhistidylpyrrolidineamide and cyclopentane carbonyl-(beta)-(2-thienyl)-L-alanine-prolineamide are competitive inhibitors of TRH-induced TSH and PRL release, since they lack structural similarity to TRH. In vivo studies whereby the inhibitory effect of thyrotropin releasing hormone diazo- and chloromethylketone analogs on TRH releasing activity in rats pre-treated with these inhibitors is measured either by I-125 release into peripheral blood, or by radioimmunoassay of serum prolactin and thyrotropin levels show that the effects of these compounds are unique to the hypothalamo-pituitary-thyroid endocrine system. The synthesis of pGluN('(tau))(3-Me)HisProNH(,2) and its corresponding diazomethylketone and chloromethylketone analogs resulted in compounds having increased inhibition of TRH-induced TSH and PRL release in vivo. Since pGluN('(tau))(3-Me)HisProNH(,2) has been shown by Vale et al to have increased PRL and TSH releasing activity in vivo and in vitro, it is interesting that diazomethyl- and chloromethylketone analogs of this compound show increased inhibition of TSH and PRL release. This leads us to believe that these compounds are demonstrating their effects through the TRH receptor. The fact that TRH-DMK shows similar inhibitory effects on TSH and PRL release in vivo suggest that the receptors responsible for these effects are very similar. Once the effect of the inhibitors on PRL and TSH release is fully understood, these compounds may serve as useful therapeutic agents in treatment of various clinical disorders such as thyrotoxicosis.
