TRH analogs with 4-nitro- and 4-N-butyloxycarbonylamino-1-methyl-2-pyrolylcarboxylic acid in position 1. Synthesis and biological properties.

Two new analogs of thyrotropin-releasing hormone (TRH), obtained by the replacement of the L-pyroglutamic acid residue with 4-nitro- or 4-N-butyloxycarbonylamino-1-methyl-2-pyrolylcarboxylic acid (analogs 1, 3), and three related derivatives, in which also the L-histidine residue was replaced with L-norvaline (analogs 2, 4) or L-norleucine (analog 5), were synthesized and tested for endocrine and central nervous system (CNS) activity. The replacement of the L-pyroglutamic acid residue with 4-nitro-1-methyl-2-pyrolylcarboxylic acid (analogs 1 and 2) resulted in the separation of the endocrine from the direct CNS activity. The effect of these analogs on the sleeping time, rectal temperature and breathing frequency, was either the same or greater than that of TRH. However, neither the correlation between the binding of analogs to TRH receptors in the brain nor their activity on the CNS parameters measured was found. Analogs 3, 4 and 5, containing 4-N-butyloxycarbonylamino-1-methyl-2-pyrolylcarboxylic acid in place of L-pyroglutamic acid, were inactive.