Synthesis of thyrotropin-releasing hormone analogs with selective central nervous system effects

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Abstract
Thyrotropin-releasing hormone (TRH) analogs which show relative selectivity for action in the CNS [antidepressant activity in man and animals] were recognized. Practical syntheses for 3 of these TRH analogs which show the greatest selectivity (< Aad-His-Tzl-NH2 [.alpha.-aminoadipyl histidylthiazolidine-4-carboxylic acid amide], < Glu-His-Pip-OMe [pyroglutamylhistidyl methoxy pipecolic acid] and < Aad-His-Pro-NH2 (6) [.alpha.-aminoadipylhistidy prolinamide]) are described. The first 2 were prepared by solution methods of peptide synthesis. Compound 6 was prepared by the solid-phase method. Problems of histidine racemization, facile diketopiperazine formation and instability of acylated thiazolidine carboxylic acid derivatives under acidic conditions were minimized to attain optimal yields. Physical properties (e.g., pK, NMR shifts and circular dichroism) were examined as they might relate to biological activity and peptide conformation.

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