Abstract: Betides having at least one betidamino acid are provided which have GnRH antagonistic properties. These antagonists may be used to regulate fertility and to treat steroid-dependent tumors, such as prostatic and mammary tumors. One particularly effective betide, which is an analog of the decapeptide GnRH that is highly soluble in water at physiologic pH, has the formula: Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-Aph(acetyl)-D-Aph(acetyl)-Leu-D/L-Agl(methyl,i sopropyl .beta.-alanyl)-Pro-D-Ala-NH.sub.2, and another has the formula Ac-D-2Nal-D-Cpa-D-3Pal-D/L-Agl(For)-Aph(Ac)-D-Aph(Ac)-Leu-ILys-Pro-D-Ala-N H.sub.2.

Abstract: Novel cyclic CRF antagonist peptides are created by shortening the N-terminus of a CRF family peptide by 8-11 residues and adding an acyl group. CML is preferably present in what would be the 27-position of the native CRF sequence, and D-Tyr may be incorporated at the N-terminus to facilitate labelling. The cyclizing bond is preferably created between the side chains of the residues in positions 30 and 33; but it may alternatively be created between the residues in either of positions 28 and 29 with those in positions 31 and 32 or with those in positions 32 and 33, respectively. The side chain of Lys in position 33 is preferably linked to the side chain of Glu in position 30 by a lactam bridge to form the cyclic peptide. Disclosed CRF antagonists include:(cyclo 30-33) ?Ac-Asp.sup.9, D-Phe.sup.12, Nle.sup.21,38, CML.sup.27,40, Glu.sup.30, Lys.sup.33 !r/hCRF(9-41),(cyclo 30-33) ?Ac-Asp.sup.9, D-Phe.sup.12, Nle.sup.21,38, CML.sup.27,37, Glu.sup.30, Lys.sup.33 !r/hCRF(9-41),(cyclo 30-33) ?Ac-Asp.sup.9, D-Phe.sup.

Abstract: Analogs of SRIF which are selective for SSTR1 in contrast to the other cloned SRIF receptors. These analogs are useful in determining the tissue and cellular expression of the receptor SSTR1 and its biological role in the endocrine, exocrine and nervous system, as well as in regulating tumor growth. SRIF analog peptides, such as des-AA.sup.1,2,5 ?D-Trp.sup.8, IAmp.sup.9 !-SRIF inhibit the binding of ?.sup.125 I-Tyr.sup.11 !SRIF to the cloned human receptor SSTR1 but do not bind to mouse SSTR2 and SSTR3, human SSTR4 or rat SSTR5. By incorporating an iodinated tyrosine in position-2 in these selective SRIF analogs, a labelled compound useful in drug-screening methods is provided.

Abstract: Peptides which include unnatural amino acids and which either promote or inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such peptides that are GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads and may be used to treat steroid-dependent tumors. The agonists can be used for control of reproduction processes, to treat precocious puberty, endometriosis, and the like. The peptides are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-, 5-, 6- and/or 8-positions.

Abstract: Methods of making unnatural amino acids are provided which unnatural amino acids can be incorporated into peptides which either inhibit or promote the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. These unnatural amino acids are useful in the synthesis of peptides and have the formula (a): ##STR1## where W is (CH.sub.2) or ##STR2## n is an integer from 1 to 6; j=1, 2 or 3, and preferably, Y is N--CN, X is NH and R.sub.2 is alkyl, modified alkyl, alkenyl, alkynyl, aryl or methyl pyridyl. Disclosed are peptides that are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-, 5-, 6- and/or 8-positions.

Abstract: Substantially pure conotoxins are provided which inhibit synaptic transmissions at the neuromuscular junctions and which are useful both in vivo and in assays because they specifically target particular receptors, such as the acetylcholine receptor, and ion channels. The peptides are of such length that they can be made by chemical synthesis. They also may be made using recombinant DNA techniques, and the DNA encoding such conotoxins having pesticidal properties can be incorporated as plant defense genes into plant species of interest.

Abstract: Compounds are provided termed "betides" which mimic peptides and which contain one or more residues of aminoglycine, C.sup..alpha. -aminoalanine, aminosarcosine or the like wherein the side chain amino group has been acylated and optionally also alkylated. Generally, betides have the formula:X.sub.N --X.sub.1 --X.sub.2 --X.sub.3 --X.sub.m --X.sub.4 --X.sub.5 --X.sub.6 --X.sub.C, where X.sub.N is an acyl or other N-terminal group or a peptide up to about 50 amino acids in length having such a group; X.sub.C is OH, NH.sub.2 or other C-terminal group or a peptide up to about 50 amino acids in length having such a group; and X.sub.1 -X.sub.6 are each independently a betide amino acid or .alpha.-amino acid or des-X; and X.sub.m is a peptide up to about 50 amino acids or des-X; provided however that at least one of X.sub.1 -X.sub.6 is a betide amino acid residue having the formula: ##STR1## wherein R.sub.o is H or CH.sub.3, R and R.sub.2 are H or lower alkyl, and R.sub.

Abstract: Improved CRF antagonist peptides have the formula: ##STR1## wherein R.sub.30 is Cys or Glu; R.sub.33 is Cys, Lys or Orn; provided that when R.sub.30 is Cys, R.sub.33 is Cys and when R.sub.30 is Glu, R.sub.33 is Lys or Orn. The N-terminus may be extended by Asp-Leu-Thr. Lys may be substituted for Arg.sup.23 and its side chain connected by a lactam bridge to Glu.sup.20 to form a dicyclic peptide. Specific CRF antagonists disclosed include (cyclo 30-33) [D-Phe.sup.12, Nle.sup.21,38, Glu.sup.30, Lys.sup.33 ]rCRF(12-41); (cyclo 30-33) [D-Phe.sup.12, Nle.sup.21,38, Glu.sup.30, Orn.sup.33 ]rCRF(12-41), (cyclo 30-33) [D-Phe.sup.12, Nle.sup.21,38, Cys.sup.30,33 ]rCRF (12-41) and (bicyclo 20-23,30-33) [D-Phe.sup.12, Nle.sup.21,38, Lys.sup.23,33, Glu.sup.30 ]-rCRF(12-41).

Abstract: Peptides which include unnatural amino acids and which either promote or inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such peptides that are GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads and may be used to treat steroid-dependent tumors. The agonists can be used for control of reproduction processes, to treat precocious puberty, endometriosis, and the like. The peptides are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-, 5-, 6- and/or 8-positions.

Abstract: Centrally truncated NPY cyclic peptide analogs are described which have selective bioactivity for NPY Y1 receptors. Methods are provided for diagnosing physiological disorders manifested by abnormal levels of endogenous Y1 receptors, by means of measuring the amount of a NPY Y1 specific cyclic peptide analog which binds to a biological sample, and by means of administering a radiolabelled NPY Y1 specific cyclic peptide analog to a host subject followed by radiographic imaging. A method is further provided for therapeutic use of the cyclic peptide NPY analogs in clinical treatment of hypotension and anorexia.

Abstract: Methods of making unnatural amino acids are provided which unnatural amino acids can be incorporated into peptides which either inhibit or promote the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. These unnatural amino acids are useful in the synthesis of peptides and have the formula (a): ##STR1## where W is (CH.sub.2).sub.n or ##STR2## n is an integer from 1 to 6; j=1, 2 or 3, and preferably, Y is N--CN, X is NH and R.sub.2 is alkyl, modified alkyl, alkenyl, alkynyl, aryl or methyl pyridyl. Disclosed are peptides that are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-, 5-, 6- and/or 8-positions.

Abstract: Mammalian melanin-concentrating hormone (MCH) is isolated from rat tissue, purified and characterized. These MCH peptides are useful for treating skin disorders, for suppressing the proliferation of skin tumor cells, such as melanomas in mammals, and for modulating the secretion of ACTH. Generally, peptides are provided which have the following formula: ##STR1## or which are naturally occurring homologs of the peptide with said formula. The peptides which are the naturally occurring MCH homologs of mammalian species other than rat can also be obtained using the materials disclosed, as demonstrated specifically with human MCH, which is found to have the same structure as rat MCH. Also disclosed are the amino acid sequences of, and the nucleotide sequences of the cDNAs which encode, the putative precursors of rat MCH and human MCH. These precursors may also include one or more biologically active peptides N-terminally of the mature MCH's.

Abstract: Analogs of the decapeptide GnRH which include two significantly modified amino acids at positions 5 and 6 inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads and may be used to treat steroid-dependent tumors. Particularly effective peptides which are soluble in water at physiologic pH and which have a low tendency to gel when administered in vivo have the following formula:Ac-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Q.sub.1)(3-amino-1,2,4 triazole)-D-Aph(Q.sub.2)(3-amino 1,2,4-triazole)-Leu-Lys (isopropyl)-Pro-D-Ala-NH.sub.2,where Q.sub.1 and Q.sub.2 are amino acids, such as Gly, .beta.-Ala, Ala, D-Ala, Ser, Aib, Ahx and Gab. Examples of other GnRH antagonists includeAc-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Atz)-D-Aph(Ac)-Leu-Lys(isopropyl )-Pro-D-Ala-NH.sub.2,Ac-.beta.

Abstract: Improved CRF peptide antagonists have the formula: ##STR1## wherein R.sub.20 is Cys or Glu; R.sub.23 is Cys, Lys or Orn; provided that when R.sub.20 is Cys, R.sub.23 is Cys and when R.sub.20 is Glu, R.sub.23 is Lys or Orn; or a nontoxic addition salt thereof. Specific CRF antagonists disclosed include (cyclo 20-23) [D-Phe.sup.12, Lys.sup.23, Nle.sup.21,38, ]rCRF(12-41); (cyclo 20-23) [D-Phe.sup.12, Orn.sup.23, Nle.sup.21,38 ]rCRF(12-41) and (cyclo 20-23) [D-Phe.sup.12, Cys.sup.20, Cys.sup.23, Nle.sup.21,38 ]rCRF(12-41).

Abstract: Mammalian melanin-concentrating hormone (MCH) is isolated from rat tissue, purified and characterized. These MCH peptides are useful for treating skin disorders, for suppressing the proliferation of skin tumor cells, such as melanomas in mammals, and for modulating the secretion of ACTH. Generally, peptides are provided which have the following formula: ##STR1## or which are naturally occurring homologs of the peptide with said formula. The peptides which are the naturally occurring MCH homologs of mammalian species other than rat can also be obtained using the materials disclosed, as demonstrated specifically with human MCH, which is found to have the same structure as rat MCH. Also disclosed are the amino acid sequences of, and the nucleotide sequences of the cDNAs which encode, the putative precursors of rat MCH and human MCH. These precursors may also include one or more biologically active peptides N-terminally of the mature MCH's.

Abstract: Analogs of CRF, which are based upon hCRF, oCRF and alpha-helical CRF, are disclosed that can be administered to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels. Analogs include those having the formula (see SEQ ID NO:9): Y-Ser-Xaa.sub.2 -Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Xaa.sub.12 -His-Leu-Leu-Arg-Glu-Val-Leu-Xaa.sub.20 -Xaa.sub.21 -Xaa.sub.22 -Xaa.sub.23 -Xaa.sub.24 -Xaa.sub.25 -Gln-Leu-Ala-Gln-Gln-Ala-Xaa.sub.32 -Ser-Asn-Arg-Xaa.sub.36 -Leu-Xaa.sub.38 -Xaa.sub.39 -Ile-Xaa.sub.41 -NH.sub.2, wherein Y is an acyl group having 7 or fewer carbon atoms or hydrogen; Xaa.sub.2 is Glu or Gln; Xaa.sub.12 is Phe or D-Phe; Xaa.sub.20 is Ala or Glu; Xaa.sub.21 is Met or Nle; Xaa.sub.22 is Ala or Thr; Xaa.sub.23 is Arg or Lys; Xaa.sub.24 is D-Ala or Ala; Xaa.sub.25 is Glu or Asp; Xaa.sub.32 is D-His or His; Xaa.sub.36 is Lys or Arg; Xaa.sub.38 is Met, Nle or Leu; Xaa.sub.39 is Ala, Glu or Asp; Xaa.sub.

Abstract: Substantially pure conotoxins are provided which inhibit synaptic transmissions at the neuromuscular junctions and which are useful both in vivo and in assays because they specifically target particular receptors, such as the acetylcholine receptor, and ion channels. The peptides are of such length that they can be made by chemical synthesis. They also may be made using recombinant DNA techniques, and the DNA encoding such conotoxins having pesticidal properties can be incorporated as plant defense genes into plant species of interest.

Abstract: Peptides which have substantial bioactivity to inhibit the secretion of gonadotropins by the pituitary gland and to inhibit the release of steroids by the gonads. Administration of an effective amount of such GnRH antagonists prevents ovulation and/or the release of steroids by the gonads. They may also be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides are bicyclic analogs of the decapeptide GnRH having two covalent bonds, between the residues in the 4- and 10-positions and the residues in the 5- and 8-positions. The latter linkage includes peptide bonds between a residue of an .alpha.-amino acid outside of the main chain and a side-chain carboxyl group of the 5-position residue and a side-chain amino group of the 8-position residue.

Abstract: Unnatural amino acids are provided which can be incorporated into peptides which either inhibit or promote the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. These unnatural amino acids are useful in the synthesis of peptides and have the formula (a): ##STR1## where W is (CH.sub.2).sub.n or ##STR2## n is an integer from 1 to 6; j=1,2 or 3, and preferably, Y is N--CN, X is NH and R.sub.2 is alkyl, modified alkyl, alkenyl, alkynyl, aryl or methyl pyridyl; or the formula (b): ##STR3## where R.sub.11 is H or acyl and W is as defined in (a), and preferably R.sub.11 is H and W is ##STR4## Disclosed are peptides that are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-, 5-, 6- and/or 8-positions.

Abstract: Human Neuropeptide Y (NPY) has the formula: H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro- Ala-Glu-Asp-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile- Thr-Arg-Gln-Arg -Tyr-NH.sub.2. Porcine and rat NPY have the same sequence except for Leu instead of Met in the 17-position. Porcine PYY is homologous having 11 different residues. NPY analogs and N-terminally-shortened fragments, e.g. NPY(18-36), which contain one or more specific D-isomer substitutions for the naturally occurring residues (as well as pharmaceutically acceptable salts thereof), dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals, including humans, to substantially lower blood pressure over an extended period of time or to counteract hypertension.