CHARACTERIZATION OF A NOVEL AND POTENT CORTICOTROPIN-RELEASING FACTORANTAGONIST IN RATS

The present study examined the ability of two analogs of human/rat cor ticotropin-releasing factor (h/rCRF), [Met(18),Lys(23),Glu(27,29,40,)A la(32,41) Leu(33,36,38)] h/rCRF(9-41) (alpha-hel CRF(9-41)) and [D-Phe (12),Nle(21,38),C-alpha MeLeu(37)] h/TCRF(12-41) (D-Phe CRF(12-41)), t o antagonize CRF- and stress-induced behavioral changes in rats. The p otency and duration of action of D-Phe CRF(12-41) in vivo was compared with that of alpha-hel CRF(9-41), the most effective CRF antagonist s tudied to date. When administered i.c.v., both CRF antagonists dose-de pendently reduced the locomotor activity induced by rat CRF (0.5 mu g/ rat i.c.v.) and attenuated the social stress-induced anxiogenic-like e ffect, as measured by the elevated plus-maze. However D-Phe CRF(12-41) was 5 times more potent and remained effective for a longer period (> 1.5 hr) than cu-hel CRF(9-41) High doses of a-her CRF(9-41) (25 mu g/ rat), by itself, exhibited weak agonist effects, which were not observ ed with D-Phe CRF(12-41) at the same doses. These results demonstrate that a N-terminus-shortened CRF antagonist that encompasses the substi tution D-Phe(12) has significantly higher biological potency and an ex tended duration of action without intrinsic agonist effects in these i n vivo systems. The availability of potent and effective CRF antagonis ts will provide valuable tools for exploring the functional role of br ain CRF and may ultimately lead to an understanding of the biological basis of stress-related illnesses.