81018-79-3Relevant academic research and scientific papers
Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice
Meena, Chhuttan L.,Ingole, Shubdha,Rajpoot, Satyendra,Thakur, Avinash,Nandekar, Prajwal P.,Sangamwar, Abhay T.,Sharma, Shyam S.,Jain, Rahul
, p. 56872 - 56884 (2015/07/15)
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-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 evaluated in vivo by using the antagonism of a pentobarbital-induced sleeping time. The peptides 6a, 6c and 6e were 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, 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).
Synthesis, receptor binding, and activation studies of N(1)-alkyl-l-histidine containing thyrotropin-releasing hormone (TRH) analogues
Kaur, Navneet,Monga, Vikramdeep,Josan, Jatinder S.,Lu, Xinping,Gershengorn, Marvin C.,Jain, Rahul
, p. 5981 - 5988 (2007/10/03)
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 μM 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 μM but could only activate TRH-R1 at EC50 value of 1.6 μM; 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.
Facile one-step synthesis of N-α-Boc-1-alkyl-l-histidines
Kaur, Navneet,Monga, Vikramdeep,Jain, Rahul
, p. 6883 - 6885 (2007/10/03)
A convenient one-step synthesis of N-α-Boc-1-alkyl-l-histidines 2a-f starting from Boc-l-histidine is described. N-α-Boc-l-Histidine upon direct τ(N-1) ring alkylation with various alkyl halides in the presence of sodium hydride in DMF or CH3CN easily afforded N-α-Boc-1-alkyl- l-histidines 2a-f. The reaction works equally well in either DMF or CH 3CN as solvent, however, CH3CN is preferred due to ease of reaction work-up.
Aggregation Behavior of Amphiphiles Functionalized with Dipeptide Segments and Enantioselective Ester Hydrolysis in Their Bilayer Membranes
Murakami, Yukito,Nakano, Akio,Ikeda, Hidetsugu,Imori, Toru,Akiyoshi, Kazunari
, p. 172 - 180 (2007/10/02)
Four amphiphiles having dipeptide segments, which consist of one histidyl residue and another amino acid residue, and the dihexadecyl moiety for the double-chain segment (N+C5AlaHis2C16, N+C5LeuHis2C16, N+C5PheHis2C16, and N+C5HisAla2C16) were synthesized, and the aggregate morphology of them was characterized by electron microscopy and differential scanning calorimetry.The amphiphiles, which have the histidyl residue bound to the dihexadecylamine component (N+C5AlaHis2C16, N+C5LeuHis2C16, and N+C5PheHis2C16) formed both multi- and single-walled aggregates in the aqueous dispersion state, while their sonicated solutions involved only single-walled vesicles.On the other hand, the amphiphile, which has the alanyl residue bound to the dihexadecylamine component (N+C5HisAla2C16) afforded tubular aggregates in the aqueous dispersion.The hydrolysis of enantiomeric esters of various hydrophobic nature, which was carried out in the single-walled vesicles, showed relatively small enantioselectivity.The reasons for such catalytic performance of the vesicles were discussed from the kinetic and mechanistic viewpoints; the kinetic analysis being carried out on the basis of the organic pseudo-phase concept.
