Experimental and clinical observations have supported the concept that the hypothalamus plays a key role in the regulation of adenohypophysial corticotropic cells' secretory functions. Over 25 years ago it was demonstrated that factors present in the hypothalamus would increase the rate of ACTH secretion by the pituitary gland when incubated in vitro or maintained in an organ culture. However, a physiologic corticotropin releasing factor (CRF) was not characterized until ovine CRF (oCRF) was characterized in 1981. As disclosed in U.S. Pat. No. 4,415,558, the disclosure of which is incorporated herein by reference, oCRF was found to be a 41-residue amidated peptide. oCRF lowers blood pressure in mammals when injected peripherally and stimulates the secretion of ACTH and .beta.-endorphin.
Rat CRF (rCRF) was later isolated, purified and characterized; it was found to be a homologous, amidated hentetracontapeptide as described in U.S. Pat. No. 4,489,163, the disclosure of which is incorporated herein by reference. The formula of human CRF has now been determined to be the same as that of rCRF, and the terms rCRF and hCRF are used interchangeably.
A CRF analog was subsequently developed having a high alpha-helical forming potential which is also a 41-residue amidated peptide. It is commonly referred to as AHC (alpha-helical CRF) and is described in U.S. Pat. No. 4,594,329, the disclosure of which is incorporated herein by reference. Other analogs containing D-isomers were developed, such as those shown in U.S. Pat. No. 5,278,146.
Synthetic rCRF, oCRF and AHC stimulate ACTH and .beta.-endorphin-like activities (.beta.-END-Li) in vitro and in vivo and substantially lower blood pressure when injected peripherally. Antagonists of these compounds are disclosed in U.S. Pat. No. 4,605,642, issued Aug. 12, 1986, the disclosure of which is incorporated herein by reference. Cyclic CRF analogs exhibiting biopotency have been developed as disclosed in U.S. Pat. No. 5,245,009 (Sep. 14, 1993) and in pending U.S. patent application Ser. No. 78,558, filed Jun. 16, 1993, now U.S. Pat. No. 5,493,006.
Since the foregoing discoveries, the search for improved CRF analogs has continued.