In addition to governing the release of thyrotropin and prolactin from the pituitary, TRH (Lpyroglutamyl-L-histidinyl-L-proline amide) is known to exert a wide variety of effects on both the central nervous system (CNS) and the cardiovascular system (CVS). TRH has shown promise in the treatment of circulatory shock and/or CNS ischemic damage, as a promoter of 1, the regeneration of injured spinal cord, as an antidepressant and in the amelioration of symptoms associated with amylotrophic lateral sclerosis (ALS). However, the great variety of its biological effects presents a serious drawback to its use as a specific drug. Our early studies with synthetic analogues of TRH (involving modification of the imidazole ring of histidine) have suggested that some of the central actions of TRH are not mediated through high affinity TRH receptors and that appropriate analogues may achieve desired specificity of action. Receptor binding studies with these analogues has made it clear that endocrine and various ,centrally mediated actions of TRH involve uniquely different mechanisms and that after a decade of effort in various laboratories, separation of these activities has been achieved. Thus, 4(5)-NO(2)-Im-TRH is highly selective for CVS activity and may be useful in the treatment of various forms of shock without any endocrine effects. Similarly, Nva(2)-TRH is a selective analeptic compound without any effects on cardiovascular system and has served as a useful research tool in delineating binding sites in rat brain which possibly mediate the analeptic effects of TRH and its analogues. Computer assisted structure-activity analysis of various imidazole-substituted analogues has helped us to design more selective and potent analogues as well as photoaffinity labels for TRH receptors. Recently we have carried out receptor binding, analysis of various TRH analogues with subtle backbone modifications (replacement of peptide bond with thioamide surrogate) and have been able to identify subtle differences in the high affinity TRH receptors in rat pituitary and brain. Further receptor analysis and pharmacological studies with these compounds are expected to provide more insight into the mechanism of TRH actions.
