title: Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice.
abstract: TRH-like peptides were synthesized in which the criticalN-terminus residue L-pGlu was replaced with various heteroaromatic rings, and the central residue histidine with 1-alkyl-L-histidines. All synthesized TRH-like peptides were evaluatedin vitroas agonists in HEK mTRH-R1 and HEK mTRH-R2 cell lines, an expressing receptor binding assay (IC50), and cell signaling assay (EC50). The analeptic potential of the synthesized peptides was evaluatedin vivoby using the antagonism of a pentobarbital-induced sleeping time. The peptides6a,6cand6ewere found to activate TRH-R2 with potencies (EC50) of 0.002 μM, 0.28 μM and 0.049 μM,respectively. In contrast, for signaling activation of TRH-R1, the same peptides required higher concentration of 0.414 μM, 50 μM and 19.1 μM, respectively in the FLIPR assay. The results showed that these peptides were 207, 178 and 389-fold selective towards TRH-R2 receptor subtype. In the antagonism of a pentobarbital-induced sleeping time assay, peptide6cshowed a 58.5% reduction in sleeping time. The peptide6cexhibited high stability in rat blood plasma, a superior effect on the scopolamine-induced cognition impairment mice model, safe effects on the cardiovascular system, and general behavior using a functional observation battery (FOB).
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
authors.forename: Chhuttan L
authors.initials: CL
authors.lastname: Meena
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
authors.forename: Shubdha
authors.initials: S
authors.lastname: Ingole
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
authors.forename: Satyendra
authors.initials: S
authors.lastname: Rajpoot
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
authors.forename: Avinash
authors.initials: A
authors.lastname: Thakur
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
authors.forename: Prajwal P
authors.initials: PP
authors.lastname: Nandeker
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Sharma
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, 160 062, Punjab, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Jain