Two novel thioamide analogues of TRH with selective activity on CNS.

TRH analogues containing C-terminal tioamide group and norvaline (Nva2, Prot3] TRH) or norleucine (Nle2, Prot3] TRH) in position 2 were synthesized and tested for hormonal and central nervous system (CNS) activities. Receptor binding studies revealed that the analogues neither bind to pituitary nor to brain TRH receptors. Accordingly, no TSH releasing activity was recorded. However, both analogues significantly affected sleeping time and breathing frequency. Dissociation of endocrine effects from those on the CNS of Prot3] TRH was achieved with the replacement of histidine2 by aliphatic amino acids. The presence of central histidine is not essential for the analogues to be active on the CNS.