US 4,605,642 AGranted

CRF antagonists

AssigneeThe Salk Institute for Biological Studies

InventorsCatherine L. Rivier, Jean E. F. Rivier, Wylie W. Vale, Jr., Marvin R. Brown

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Abstract

Several polypeptide analogs of the known members of the corticotropin releasing factor (CRF) family have been synthesized and tested including human and rat CRF which have the formula: H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val- Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu -Met-Glu-Ile-Ile-NH.sub.2. Peptides are herein disclosed that are potent competitive antagonists of CRF in mammals. One which has been found to be particularly potent is: H-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Leu-Glu-Met-Ala-Lys-Ala-Glu- Gln-Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn-Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH.sub.2. These antagonists or pharmaceutically or veterinarily acceptable salts thereof, dispersed in a pharmaceutically or veterinarily acceptable liquid or solid carrier, can be administered to mammals, including humans, to achieve a prevent elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels and/or a lowering of brain-mediated responses to stress over an extended period of time. They may also be used to affect mood, memory and learning, as well as diagnostically.

Claims20

Dependent claims

A composition for lowering stressinduced secretion of ACTH, .beta.-endorphin, .beta.-lipotropin and proopiomelanocortin-related peptides in mammals comprising an effective amount of a synthetic peptide or a nontoxic addition salt thereof having the sequence:

R.sub.8 -R.sub.9 -leu-R.sub.11 -R.sub.12 -R.sub.13 -leu-leu-Arg-R.sub.17 -R.sub.18 -R.sub.19 -Glu-R.sub.21 -R.sub.22 -R.sub.23 -R.sub.24 -R.sub.25 -R.sub.26 -R.sub.27 -R.sub.28 -R.sub.29 -Gln-ala-R.sub.32 -R.sub.33 -Asn-Arg-R.sub.36 -R.sub.37 -R.sub.38 -R.sub.39 -R.sub.40 R.sub.41 wherein R.sub.8 is ala, Gly, Gln, Ile, leu, Nle, Phe, Val or des-R.sub.8;
R.sub.9 is Asp, Glu or des-R.sub.9;
R.sub.12, R.sub.19 and R.sub.24 are selected from the group consisting of leu, Ile, ala, Asn, Gly, Val, Nle, Phe and Gln;
R.sub.11 is Thr or Ser;
R.sub.13 is His, Tyr or Glu;
R.sub.17 is Glu, Asn or Lys;
R.sub.18 is Val, Nle or Met;
R.sub.21 is Met, Nva, Ile, ala, leu, Gly, Nle, Val, Phe or Gln;
R.sub.22 is ala or Thr or Glu;
R.sub.23 is Arg, Orn, and Har or Lys;
R.sub.25 is Asp or Glu;
R.sub.26 is Gln, Asn or Lys;
R.sub.27 is leu, Ile, ala, Val, Nva, Met, Nle, Phe, Asp, Asn, Gln or Glu;
R.sub.28 is ala, Arg or Lys;
R.sub.29 is Gln or Glu, R.sub.32 is His, Gly, Tyr or ala;
R.sub.33 is Ser, Asn, leu, Thr or ala;
R.sub.36 is Lys, Orn, Arg, Har or leu;
R.sub.37 is leu or Tyr;
R.sub.38 is Met or leu;
R.sub.39 is Glu or Asp;
R.sub.40 is Ile, Thr, Glu, ala, Val, leu, Nle, Phe, Nva, Gly or Gln;
and R.sub.41 is ala, Ile, Gly, Val, leu, Nle, Phe, Nva or Gln;
ala representing either L-Ala or C.alpha.CH.sub.3 -L-Ala and leu representing either L-Leu or C.alpha.CH.sub.3 -L-Leu;
and a pharmaceutically or veterinarily acceptable liquid or solid carrier therefor.

21 more elements

Dependencies are inferred from the claim text.