Synthesis, receptor binding, and activation studies of N(1)-alkyl-L-histidine containing thyrotropin-releasing hormone (TRH) analogues

Bioorg Med Chem. 2006 Sep 1;14(17):5981-8. doi: 10.1016/j.bmc.2006.05.031. Epub 2006 Jun 2.

Abstract

Thyrotropin-releasing hormone (TRH) analogues in which the N(1)-position of the imidazole ring of the centrally placed histidine residue is substituted with various alkyl groups were synthesized and studied as agonists for TRH receptor subtype 1 (TRH-R1) and subtype 2 (TRH-R2). Analogue 3 (R=C2H5) exhibited binding affinity (Ki) of 0.012 microM to TRH-R1 that is about 1.1-fold higher than that of TRH. Several analogues were found to selectively activate TRH-R2 with greater potency than TRH-R1. The most selective agonist of the series 5 [R=CH(CH3)2] was found to activate TRH-R2 with a potency (EC50) of 0.018 microM but could only activate TRH-R1 at EC50 value of 1.6 microM; that is, exhibited 88-fold greater potency for TRH-R2 versus TRH-R1. The results of this study indicate that modulation of central histidine residue is important for designing analogues which were selective agonist at TRH receptor subtypes.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Histidine / analogs & derivatives*
  • Histidine / metabolism*
  • Molecular Structure
  • Protein Binding
  • Receptors, Thyrotropin-Releasing Hormone / metabolism*
  • Thyrotropin-Releasing Hormone / analogs & derivatives*
  • Thyrotropin-Releasing Hormone / chemical synthesis
  • Thyrotropin-Releasing Hormone / chemistry
  • Thyrotropin-Releasing Hormone / metabolism*

Substances

  • Receptors, Thyrotropin-Releasing Hormone
  • Histidine
  • Thyrotropin-Releasing Hormone