Neuropharmacodynamic evaluation of the centrally active thyrotropin-releasing hormone analogue [Leu2]TRH and its chemical brain-targeting system.

The centrally active thyrotropin-releasing hormone (TRH) analogue pGlu-Leu-Pro-NH(2) ([Leu(2)]TRH) showed a significant increase in the extracellular acetylcholine concentration during its perfusion to the hippocampus in rats, and this effect was manifested upon the delivery of the analogue in much smaller quantities compared to TRH when measured by in vivo intracranial microdialysis. The neuropharmacodynamic efficacy of [Leu(2)]TRH upon intravenous administration was augmented by the use of a brain-targeting derivative in which the progenitor sequence of the mature peptide was embedded in a molecular architecture that promoted enhanced brain delivery, retention and in situ generation of the pharmacologically active molecule. Compared to the unmodified peptide, the targeting system significantly improved the cumulative effect of the treatment on extracellular acetylcholine levels in rats.