STRUCTURE ACTIVITY RELATIONSHIP STUDIES WITH HYPOTHALAMIC PEPTIDE-HORMONES .2. EFFECTS OF THYROTROPIN RELEASING HORMONE ANALOGS ON MORPHINE-INDUCED RESPONSES IN MICE

The effects of several analogs of TRH, that have a chloroacetyl substituent at the amino terminus, on locomotor depressant, locomotor stimulant, hyperthermic and hypothermic response to morphine were determined in the mouse. These compounds included N-(chloroacetyl)-L-phenylalanylpyrrolidine (CIAc-Phe-Pyrr), N-[m-(chloroacetyl)benzoyl]-L-phenylalanylpyrrolidine (mCIAcBz-Phe-Pyrr), N-[m-(chloroacetyl)benzoyl]-L-alanyl-L-phenylalanylpyrrolidine(mCIAcBz-Ala-Phe-Pyrr),N-[p-(chloroacetyl)benzoyl]-L-alanyl-L-phenylalanyl-pyrrolidine (pCIAcBz-Ala-Phe-Pyrr), N-(chloroacetyl)-L-alanyl-L-phenylalanyl-L-prolineamide(CIAc-Ala-Phe-Pro-NH2), N-[m-(chloroacetyl)-benzoyl]-L-phenylalanyl-L-prolineamide (mCIAcBz-Phe-Pro-NH2), N-[p-(chloroacetyl)benzoyl]-L-phenylalanyl-L-prolineamide (pCIAcBz-Phe-Pro-NH2). Since TRH is metabolized to cyclo (His-Pro) and the latter is shown to possess TRH like activity, an analog cyclo (Phe-Pro) was also used. Administration of morphine to mice at 10 mg/kg i.p. produced hyperthermia and depression in locomotor activity, while at 80 mg/kg i.p., hypothermia and stimulation in locomotor activity were observed. Intracerebral injection of the following peptides (10 .mu.g each per mouse) administered 10 min prior to morphine injection antagonized locomotor depression, hyperthermia, locomotor stimulation and hypothermia induced by an appropriate dose of morphine: mCIAcBz-Phe-Pyrr, pCIAcBz-Ala-Phe-Pyrr, CIAcAla-Phe-Pro-NH2, pCIAcBz-Phe-Pro-NH2, cyclo (Phe-Pro) and TRH. The compounds which had no effect on low dose or high dose morphine induced responses included pGlu-Phe-Pyrr, and mCIAcBz-Phe-Pro-NH2, pCIAcBz-Phe-Pro-NH2, cyclo (Phe-Pro) and TRH. mCIAcBz-Ala-Phe-Pyrr CIAc-Phe-Pyrr antagonized morphine-induced locomotor stimulation and hypothermia but did not affect locomotor depression and hyperthermia produced by morphine. None of these peptides had any effect on the body temperature or the locomotor activity of normal mice. Many of the active compounds were previously shown to possess extremely weak or no activity in releasing TSH from the pituitary. Several of these TRH analogs possess CNS activity in antagonizing morphine effects, and a lack of relationship exists between the CNS and endocrine activity of these peptides.