Regulatory peptides as a source of new drugs--the clinical prospects for analogues of TRH which are resistant to metabolic degradation.

The biological properties of several analogues of TRH (Pyr-His-Pro X NH2) are reviewed. Analogues discussed include those with modifications to the Pyr moiety (e.g. DN-1417, CG 3509 and CG 3703), the Pro moiety (e.g. RX 77368) and MK-771 which has both terminal residues modified. The analogues have enhanced biological half-lives compared to TRH because of their resistance to enzymatic degradation. Neuropharmacological evaluation indicates the analogues to be active in antidepressant screening tests, to reverse the effects of diverse CNS depressants and to promote arousal when given alone. The analogues all exhibit enhanced potency compared to TRH in such tests. In contrast they appear equipotent to TRH in endocrine tests. An explanation is offered for this paradox in terms of metabolic stability and bioavailability to the requisite sites of action. The prospects for clinical utilization of the neuropharmacological properties common to TRH and its analogues are considered.