Synthesis of thyrotropin-releasing hormone analogs. 2. Tripeptides structurally greatly different from TRH with high central nervous system activity

Abstract

A new series of thyrotropin-releasing hormone (TRH) analogues, obtained by further modifications of our most potent central nervous system (CNS) stimulating neutral tripeptides at both termini, were synthesized by the pentafluorophenyl ester method and tested for CNS and thyrotropin (TSH) releasing activity. Replacement of pyroglutamic acid by pyro-2-aminoadipic acid, 2-oxoimidazolidine-4-carboxylic acid or gamma-butyrolactone-gamma-carboxylic acid and that of proline by pipecolic acid, thiazolidine-4-carboxylic acid, or homoproline in [Leu2]- and [Nva2]TRH led to tripeptides structurally widely different from TRH. In spite of this fact, 7 of the 17 analogues (1, 2, 8-10, 16, and 17) have stronger anticataleptic effect than TRH, with negligible or no hormonal potency. The highest CNS activity was achieved when pyroglutamic acid was replaced by pyro-2-aminoadipic acid at the N-terminus [pAad-Leu-Pro-NH2, 1 (RGH 2202), and pAad-Nva-Pro-NH2,2]. A novel synthesis of L-2-aminoadipic acid suitable for large-scale preparation is also described.

Synthesis, Receptor Binding, and CNS Pharmacological Studies of New Thyrotropin‐Releasing Hormone (TRH) Analogues

“…[28][29][30] l-pAad-OPfp (15) was synthesized from commercially available l-Lys(Z)-OH in four steps as described earlier. [31] Boc-1-alkyl-l-His-OH compounds 17 a-e were synthesized from Boc-l-His-OH in one step as reported. [32] (1R)-3-Ocp-OH (20) was synthesized from 4-vinylcyclohexene in four steps and chemically resolved using a well-established procedure.…”

Thyrotropin-Releasing Hormone Analogs

“…This result demonstrated that the presence of histidine is not essential for the CNS activity while, as mentioned above, the steric properties of the amino acid at position 2 are critical in the ligand's hormonal activity. Subsequently, it was shown [49] that further replacement of pyroglutamic acid by pyro-2-aminoadipic acid in addition to replacement of His by Leu or Nval resulted in analogs with prominent CNS activity with little or no hormonal potency.…”

The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases

“…1G) is created by substituting both the pGlu and His residues. Posatirelin is approximately 5 times more potent in regard to its CNS effects than TRH, however its effects on TSH release are diminished 30-fold compared to native TRH (Szirtes et al, 1986; Oka et al, 1989; Culum and Forbes, 2008). Posatirelin has been shown to enhance norepinephrine and dopamine turnover in the cerebral cortex, nucleus accumbens, and striatum, and increase cyclic GMP levels in the cerebellum of rats (Oka et al, 1989).…”