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

Abstract

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.

Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue

“…This is consistent with our prior study using TRH receptor knockout mice, which showed that other effects of TAL, which are also most likely mediated by receptors in the central nervous system, require the TRH 1 , but not TRH 2 , receptor [11]. Although studies have examined the effects of TRH analogs with greater or lesser in vitro potencies for the TRH 1 or TRH 2 receptor [36, 37], to our knowledge, the current study and Thirunarayanan et al [11] are the only to employ TRH receptor knockout mice to determine which TRH receptor mediates a given response to TRH. Thus, we conclude that the TRH 1 receptor is the primary mediator of the anti-fatigue effects of TRH receptor agonists.…”

Hypothalamic neurohormones and immune responses

“…Available TRH analogs have higher affinities for the TRHR, longer half-lives, etc. (Engel et al, 2006; Khomane et al, 2011; Monga et al, 2011). …”

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

“…The resulting mixture was stirred at 4 °C for 36 h. After the completion of reaction, the solvent was removed under reduced pressure, and the residue thus obtained was purified by flash column chromatography using a stationary phase of neutral alumina and a mobile phase of 6% MeOH in CH 2 Cl 2 to afford 4a–e . 33 …”