title: Synthesis and biology of ring-modified l-Histidine containing thyrotropin-releasing hormone (TRH) analogues.
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.
authors: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
authors: Chhuttan L
authors: CL
authors: Meena
authors: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
authors: Avinash
authors: A
authors: Thakur
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
authors: Prajwal P
authors: PP
authors: Nandekar
authors: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
authors: Shyam S
authors: SS
authors: Sharma
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
authors: Abhay T
authors: AT
authors: Sangamwar
authors: 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.
authors: Rahul
authors: R
authors: Jain
mesh_terms: D057809:HEK293 Cells; D006639:Histidine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000737:chemistry / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018025:Receptors, Thyrotropin-Releasing Hormone; D006639:Histidine; D013973:Thyrotropin-Releasing Hormone
keywords: Molecular modeling; Synthesis; TRH; TRH analogues; TRH receptors; TRH-DE; TSH