| An endogenous neuropeptide, TRH, has been considered a lead compound for developing agents useful for treatment of several CNS-related diseases associated with the loss of specific cholinergic nerve cell activity or the loss of nerve cells themselves (e.g., Alzheimer's disease, Lou Gehrig's disease, motorneuron diseases). To better understand the neurophysiological and neuropharmacological effects of TRH in the CNS, efforts have been put into developing TRH analogues that can antagonize TRH action in the CNS. From our earlier study, it has been shown that [Glu2]TRH can antagonize TRH action in the mammalian brain. Analogues with the central His replaced by Glu, D-Glu, Asp, D-Asp, betaGlu, betaAsp, Leu, and Gln were synthesized. These peptides were then tested alone and in a mixture with TRH (in equimolar doses) for their effect in ACh-release by microdialysis perfusion of drugs to rat hippocampus. Local perfusion of [Glu2]TRH, [Asp2]TRH, and [betaAsp2]TRH (1 nmol/muL) through microdialysis probe in the rat hippocampus did not change the basal level of extracellular ACh, but co-perfusion of these TRH analogues with TRH in equimolar concentrations attenuated TRH-induced ACh-release. The antagonism of barbiturate-induced anesthesia of these TRH-like peptides was also conducted to investigate the extent of activation of cholinergic neurons. In addition, another pharmacological evaluation method, the Porsolt's swim test, was used to study the antidepressant effect of TRH and its analogues. Among [Glu2]TRH, [Asp 2]TRH, [betaAsp2]TRH, [betaG1u2]TRH, [Gln2]TRH and [Leu2]TRH, [betaAsp2 ]TRH was the most potent and selective analogue that showed antagonism to TRH. It did not have any analeptic effect or antidepressant effect alone, but when co-administrated with TRH at equimolar doses, [betaAsp2 ]TRH antagonized the TRH-induced analeptic effect by 93% and TRH immobility time by 44%. From the results of these studies, [betaAsp2]TRH was identified as a new TRH antagonist. Details are discussed in this dissertation. |
