Azetirelin dihydrate

The transport mechanisms of thyrotropin-releasing hormone (TRH) and its pharmacologically active analogues ((3-methyl-His2)TRH (MeTRH), taltirelin, montirelin, azetirelin) across Caco-2 cell monolayers were characterized. The results of kinetic analysis showed a linear relationship between the concentration (over the range 0.5–10 mm) and apical-to-basolateral transport rate of these agents. The permeability coefficients (Papp) of these agents were not substantially different from each other, and their (Papp) ratios of the basolateral-to-apical over the apical-to-basolateral transport were close to one (0.73–1.23). The cellular transport of [3H]MeTRH at low concentrations (3–15 nm) showed a linear relationship between the concentration and transport rate. The transport of [3H]MeTRH in Caco-2 cell monolayers was neither affected by TRH nor TRH analogues, and there was little difference in (Papp) values between [3H]MeTRH and [14C]mannitol. The cell-per-medium ratio of [3H]MeTRH in the cellular uptake experiment was similar to the value of [14C]mannitol. A large excess of TRH and MeTRH did not significantly influence cell-per-medium ratios of [3H]MeTRH in Caco-2 cell monolayers. The k'IAM value, which represents lipophilicity, was decreased in the following order: montirelin > taltirelin > TRH > azetirelin, and the values varied from 0.234 to 1.028. These results indicate that a paracellular passive diffusion may be the major route for the transport of TRH and its analogues in Caco-2 cell monolayers.

The authors developed a novel diketopiperazine that shows neuroprotective activity in a variety of models, as well as in a clin. relevant exptl. model of traumatic brain injury (TBI) in rats.Treatment with 1-ARA-35b, a cyclized dipeptide derived from a modified TSH-releasing hormone (TRH) analog, significantly reduced cell death associated with necrosis (maitotoxin), apoptosis (staurosporine), or mech. injury in neuronal-glial cocultures.Rats subjected to lateral fluid percussion-induced TBI and then treated with 1 mg/kg i.v. 35b thirty minutes after trauma showed significantly improved motor recovery and spatial learning compared with vehicle-treated controls.Treatment also significantly reduced lesion volumes as shown by magnetic resonance imaging, and decreased the number of TUNEL-pos. neurons observed in ipsilateral hippocampus.Unlike TRH or traditional TRH analogs, 35b treatment did not change mean arterial pressure, body temperature, or TSH release, and did not have analeptic activity.Moreover, in contrast to TRH or typical TRH analogs, 35b administration after TBI did not alter free-magnesium concentration or cellular bioenergetic state.Receptor-binding studies showed that 35b did not act with high affinity at 50 classical receptors, channels, or transporters.Thus, 35b shows none of the typical physiol. actions associated with TRH, but possesses neuroprotective actions and appears to attenuate both necrotic and apoptotic cell death.