Hydrogen bonding interaction of thyrotropin-releasing hormone (TRH) with transmembrane tyrosine 106 of the TRH receptor.

Perlman, Jeffrey H.; Thaw, Colette N.; Laakkonen, Liisa; Cy, Bowers; Osman, Roman; Gershengorn, M C

doi:10.1016/s0021-9258(17)42069-2

Cited by 60 publications

(38 citation statements)

References 37 publications

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“…27,28 As indicated above, pGlu retains half of the peptide binding energy, therefore, we explored its replacement with some simple hetero-ring containing residues to identify its most suitable counterpart for improving stability, CNS activity and reducing hormonal activity. [29][30][31] The other objective of the replacement of the L-pGlu residue at the Nterminus was enhancing the hydrogen bonding capability at the N-terminus to note the effect on the receptor sub type selectivity. The central His residue was modied in such a way to substantially increase the hydrophobicity of the designed peptides.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

et al. 2015

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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).

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Section: Resultsmentioning

confidence: 99%

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

et al. 2015

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“…Synthesized TRH analogues were examined for their affinities for TRH-R1 and TRH-R2 and their abilities to serve as agonists of the receptors. [36] Affinities, reported as K i values (mm), were determined by measuring the concentration of the analogue required to compete with [ 3 H][Nt(1)-Me-His]TRH at 2 nm for receptor binding. [Nt(1)-Me-His]TRH is known to bind TRH-R1 and TRH-R2 with affinities higher than TRH.…”

Section: Pharmacology At Trh-r1 and Trh-r2mentioning

confidence: 99%

“…Receptor binding studies were carried out according to a procedure described previously. [36] Briefly, HEK 293EM cells stably expressing either TRH-R1 or TRH-R2 were grown in Dulbecco's modified Eagle's medium containing 10 % fetal bovine serum (FBS) and 200 mg mL À1 hygromycin. For equilibrium binding experiments, cells were seeded into 24-well plates (1.5 10 5 cells per well).…”

Section: Receptor Binding Assaysmentioning

confidence: 99%

Synthesis, Receptor Binding, and CNS Pharmacological Studies of New Thyrotropin‐Releasing Hormone (TRH) Analogues

et al. 2011

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As part of our search for selective and CNS-active thyrotropin-releasing hormone (TRH) analogues, we synthesized a set of 44 new analogues in which His and pGlu residues were modified or replaced. The analogues were evaluated as agonists at TRH-R1 and TRH-R2 in cells in vitro, and in vivo in mice for analeptic and anticonvulsant activities. Several analogues bound to TRH-R1 and TRH-R2 with good to moderate affinities, and are full agonists at both receptor subtypes. Specifically, analogue 21 a (R = CH3) exhibited binding affinities (Ki values) of 0.17 μM for TRH-R1 and 0.016 μM for TRH-R2; it is 10-fold less potent than TRH in binding to TRH-R1 and equipotent with TRH in binding to TRH-R2. Compound 21 a, the most selective agonist, activated TRH-R2 with a potency (EC50 value) of 0.0021 μM, but activated TRH-R1 at EC50 = 0.05 μM, and exhibited 24-fold selectivity for TRH-R2 over TRH-R1. The newly synthesized TRH analogues were also evaluated in vivo to assess their potencies in antagonism of barbiturate-induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues 21 a,b and 22 a,b decreased sleeping time by nearly 50 % more than TRH. These analogues also displayed potent anticonvulsant activity and provided significant protection against PTZ-induced seizures, but failed to provide any protection in MES-induced seizures at 10 μmol kg−1. The results of this study provide evidence that TRH analogues that show selectivity for TRH-R2 over TRH-R1 possess potent CNS activity.

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“…As for the C-terminus part of TRH mimetics 67–70 , 73–77 were examined. It is known that the l -prolinamide moiety is important for the formation of the hydrogen bond with Arg283 of TRH receptor , to have expression of the biological activities. In the case of the TRH mimetic having the (4 R )-4-thiazolidinecarboxamide moiety 68 , both lipophilicity (clog P = 0.131, Slog P = −0.946) and CNS effect increased.…”

Section: Resultsmentioning

confidence: 99%

“…The condensation of (4S,5S)-5methyl-2-oxooxazolidine-4-carboxylic acid (3c) (2.37 g, 16.3 mmol) and L-histidyl-L-prolinamide dihydrobromide (47) (7. 53 Hz, total 3H), 1.21 and 1.02 (d each, J = 6.6 Hz, total 3H). 13 C NMR (75 MHz, CD 3 OD): δ 170.…”

Section: ■ Summary and Conclusionmentioning

confidence: 99%

Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate)

et al. 2018

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We have explored orally effective thyrotropin-releasing hormone (TRH) mimetics, showing oral bioavailability and brain penetration by structure–activity relationship (SAR) study on the basis of in vivo antagonistic activity on reserpine-induced hypothermia in mice. By primary screening of the synthesized TRH mimetics, we found a novel TRH mimetic: l-pyroglutamyl-[3-(thiazol-4-yl)-l-alanyl]-l-prolinamide with a high central nervous system effect compared with TRH as a lead compound. Further SAR optimization studies of this lead compound led to discovery of a novel orally effective TRH mimetic: 1-{N-[(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine trihydrate (rovatirelin hydrate), which was selected as a candidate for clinical trials.

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Hydrogen bonding interaction of thyrotropin-releasing hormone (TRH) with transmembrane tyrosine 106 of the TRH receptor.

Cited by 60 publications

References 37 publications

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

Discovery of a low affinity thyrotropin-releasing hormone (TRH)-like peptide that exhibits potent inhibition of scopolamine-induced memory impairment in mice

Synthesis, Receptor Binding, and CNS Pharmacological Studies of New Thyrotropin‐Releasing Hormone (TRH) Analogues

Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate)

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