TRH Analogs: In addition to governing the release of thyrotropin and prolactin in the pituitary gland, TRH (L-pyroglutamyl-L- histidyl-L-proline amide) is known to possess a wide variety of effects on both the central nervous system (CNS) and the cardiovascular system (CVS). TRH has shown promise for use in the treatment of shock, as an analeptic and antidepressant, and as a promoter of the regeneration of injured spinal cord. However, the great variety of its biological effects presents a serious drawback to its use as a specific drug. Our early studies with synthetic analogs of TRH (involving modification of the imidazole ring of histidineO has suggested that the peptide hormone elicits each of its physiological responses at a different receptor and that appropriate analogs may achieve some of the desired specificity of action. It is now quite clear that at least four of the biological activities of TRH involve uniquely different receptors and that, after a decade of effort in various laboratories, the separation of these activities has at last been achieved. Thus, 4-NO2-Im-TRH, high selective for CVS activity, may be useful in the treatment of various forms of shock without a concomitant enhancement of thyroid activity or of prolactin release. On the other hand 2,4-I2-Im-TRH or Nva2-TRH may be useful as diagnostic tools for the assessment of pituitary function without the risk of increased blood pressure and tachycardia induced by TRH. The iodinated analog is particularly useful since it can be prepared readily with radioactive iodine. Furthermore, each of these selective agonists should provide a useful research tool for the study of the role and mechanism of TRH involvement in the respective function. Binding studies in rat brain tissue show that these analogs bind only weakly or not at all. Thus, we must search for non-TRH receptors or nonreceptor mechanisms to explain the potent cardiovascular activity of some of these analogs.