title: Modifications of the pyroglutamic acid and histidine residues in thyrotropin-releasing hormone (TRH) yield analogs with selectivity for TRH receptor type 2 over type 1.
abstract: Thyrotropin-releasing hormone (TRH) analogs in which the N-1(tau) or the C-2 position of the imidazole ring of the histidine residue is substituted with various alkyl groups and the l-pyroglutamic acid (pGlu) is replaced with the l-pyro-2-aminoadipic acid (pAad) or (R)- and (S)-3-oxocyclopentane-1-carboxylic acid (Ocp) were synthesized and studied as agonists for TRH receptor subtype 1 (TRH-R1) and subtype 2 (TRH-R2). We observed that several analogs were selective agonists of TRH-R2 showing relatively less or no activation of TRH-R1. For example, the most selective agonist of the series 13, in which pGlu is replaced with the pAad and histidine residue is substituted at the N-1 position with an isopropyl group, was found to activate TRH-R2 with a potency (EC(50)=1.9microM) but did not activate TRH-R1 (potency>100 microM); that is, exhibited >51-fold greater selectivity for TRH-R2 versus TRH-R1. Analog 8, in which pGlu is replaced with pAad and histidine is substituted at the N-1(tau) position with a methyl group, exhibited a binding affinity (K(i)=0.0032 microM) to TRH-R1 that is similar to that of [Ntau(1)-Me-His]-TRH and displayed potent activation of TRH-R1 and TRH-R2 (EC(50)=0.0049 and 0.0024 microM, respectively). None of the analogs in which pGlu is replaced with the bioisosteric (R)- and (S)-(Ocp) and the imidazole ring is substituted at the N-1(tau) or C-2 position were found to bind or activate either TRH-R1 or TRH-R2 at the highest test dose of 100 microM.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India.
authors.forename: Navneet
authors.initials: N
authors.lastname: Kaur
authors.forename: Vikramdeep
authors.initials: V
authors.lastname: Monga
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 / Q000737:chemistry*; D008968:Molecular Conformation; D011485:Protein Binding; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000819:agonists* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D018025:Receptors, Thyrotropin-Releasing Hormone; D006639:Histidine; D013973:Thyrotropin-Releasing Hormone; D011761:Pyrrolidonecarboxylic Acid