title: Synthesis, receptor binding, and activation studies of N(1)-alkyl-L-histidine containing thyrotropin-releasing hormone (TRH) analogues.
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.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.
authors.forename: Navneet
authors.initials: N
authors.lastname: Kaur
authors.forename: Vikramdeep
authors.initials: V
authors.lastname: Monga
authors.forename: Jatinder S
authors.initials: JS
authors.lastname: Josan
authors.forename: Xinping
authors.initials: X
authors.lastname: Lu
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
authors.forename: Rahul
authors.initials: R
authors.lastname: Jain
mesh_terms: D006639:Histidine / Q000031:analogs & derivatives* / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018025:Receptors, Thyrotropin-Releasing Hormone; D006639:Histidine; D013973:Thyrotropin-Releasing Hormone