2. Academic Validation
  3. Synthesis and biology of ring-modified l-Histidine containing thyrotropin-releasing hormone (TRH) analogues

Synthesis and biology of ring-modified l-Histidine containing thyrotropin-releasing hormone (TRH) analogues

  • Eur J Med Chem. 2016 Mar 23:111:72-83. doi: 10.1016/j.ejmech.2016.01.038.
Chhuttan L Meena 1,  Avinash Thakur 2,  Prajwal P Nandekar 3,  Shyam S Sharma 2,  Abhay T Sangamwar 3,  Rahul Jain 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
  • 2 Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
  • 3 Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
  • 4 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India. Electronic address: rahuljain@niper.ac.in.
PMID: 26854379 DOI: 10.1016/j.ejmech.2016.01.038
Abstract

Thyrotropin-releasing hormone (TRH) analogues bearing halogen groups (Cl, Br and I) at the C-2 and/or C-5 position, and the alkyl group (CH3, C2H5, C3H7, CH2C6H5) at the N-1 position of the imidazole ring of the central histidine residue were synthesized and evaluated for the receptor binding, calcium mobilization (FLIPR), and IP-1 assay at the HEK mTRHR1 and HEK mTRHR2 expressing cell lines. The most promising analogue 7k showed 925-fold selectivity for HEK mTRH-R2 receptor subtype in the IP-1 assay, 272-fold selectivity for HEK mTRH-R2 receptor subtype in the FLIPR assay, and 21-fold receptor binding specificity at HEK TRH-R2 receptor subtype. The peptide 7k was evaluated in vitro in a brain membrane competitive binding assay, and for stability analysis in the presence of TRH-DE, in vivo. The analogue 7k showed decrease in the sleeping time by more than 76% in a pentobarbital-induced sleeping assay, and showed comparatively less elevation in the TSH level in the blood, in vivo. The computational homology modeling of TRH-R1 and TRH-R2 and docking study with the most potent peptide 7k provide impetus to design CNS specific TRH analogues.

Keywords

Molecular modeling; Synthesis; TRH; TRH analogues; TRH receptors; TRH-DE; TSH.

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