Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in miceElectronic supplementary information (ESI) available: Complete spectral data, 1H, 13C, HPLC of all peptides and tables depicting effect of 6c on functional observation battery (FOB). See DOI: 10.1039/c5ra06935a

• Main Authors: Meena, Chhuttan L, Ingole, Shubdha, Rajpoot, Satyendra, Thakur, Avinash, Nandekar, Prajwal P, Sangamwar, Abhay T, Sharma, Shyam S, Jain, Rahul
• Format: Article
• Language: English
• ISSN: 2046-2069
• DOI: 10.1039/c5ra06935a

TRH-like peptides were synthesized in which the critical N-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 evaluated in vitro as agonists in HEK mTRH-R 1 and HEK mTRH-R 2 cell lines, an expressing receptor binding assay (IC 50 ), and cell signaling assay (EC 50 ). The analeptic potential of the synthesized peptides was evaluated in vivo by using the antagonism of a pentobarbital-induced sleeping time. The peptides 6a , 6c and 6e were found to activate TRH-R 2 with potencies (EC 50 ) of 0.002 μM, 0.28 μM and 0.049 μM, respectively. In contrast, for signaling activation of TRH-R 1 , 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-R 2 receptor subtype. In the antagonism of a pentobarbital-induced sleeping time assay, peptide 6c showed a 58.5% reduction in sleeping time. The peptide 6c exhibited 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). TRH-like peptides were synthesized in which the critical N-terminus residue l -pGlu was replaced with various heteroaromatic rings, and the central residue histidine with 1-alkyl- l -histidines.