The Salk Institute for Biological Studies

University of California

Marvin R Brown

Jean E Rivier

Wylie W Vale, Jr

Neal A Scott

Jaroslav H Boublik

Ronald Mark Evans

Catherine L Rivier

Michael G Rosenfeld

Walter E Marki

Susan G Amara

Larry Swanson

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.

NPY peptide analogs

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 wherein the N-terminus is shortened and which may contain one or more specific subsitutions for the naturally occurring residues, or 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.

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.

CRF antagonists

CGRP (calcitonin-gene-related peptide) has the formula: ##STR1## A related peptide has the residue Lys instead of Glu in the 35-position. CGRP or this homolog or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals, including humans, to influence memory, mood and pain appreciation and to achieve a substantial lowering of blood pressure or gastric acid secretion over an extended period of time. They also may be administered to affect ingestion behavior, taste and sensory perception.

Synthetic calcitonin-gene-related peptides for lowering blood pressure

Somatostatin-14 has the formula: ##STR1## Analogs that are more potent than somatostatin-14 in increasing electrolyte absorption in the gut without suppressing the secretion of GH, insulin and glucagon, or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals in the same manner as somatostatin to increase absorbtion of electrolytes for the treatment of diarrhea. In particular of the analogs, certain substitutions are made for Phe in the 11-position, sometimes in combination with deletions in the 4- and 5-positions and in the 12- and 13-positions. D-Cys may also be substituted in the 3- or 14-position. There may be some substitutions in the 6- and 10-positions, and the residues in the 1- and/or 2-positions may also be deleted or substituted.

Analogs of somatostatin

Somatostatin-28 has the formula: ##STR1## Analogs have been synthesized that are more potent than somatostatin-28, and these analogs or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals in the same manner as somatostatin. In the analogs, Leu may be substituted in the 8-position in combination with D-Trp in the 22-position and/or Tyr in the 25-position. D-Cys may also be substituted in the 28-position, and D-Ser may be substituted in the 27-position. Certain residues may also be deleted. D-Trp.sup.22 somatostation-28 has surprisingly been found to be insulin-selective when administered in vivo and is useful for the treatment of insulinoma.

Analogs of extended N-terminal somatostatin

Various peptides are described which inhibit the secretion of growth hormone by the pituitary gland and inhibit the release of glucagon and insulin by the pancreas.

Pharmaceutically active peptides

Peptides having thermoregulative and analgesic properties when administered to animals. The peptides are identified by the structure:

Bombesin analogs

Somatostatin peptides are modified by substitution of para-methoxylated Phe or para-halogenated Phe for any Phe in the peptide. The modified somatostatin peptide analogs have the formulae: ##STR1## wherein R is hydrogen or an acyl group; R.sub.1 is selected from the group consisting of Lys or Des R.sub.1 ; R.sub.2 is selected from the group consisting of Asn, Ala or Des R.sub.2. The amino acids of the R.sub.2 group can be either the L-form or the D-form; R.sub.3 is selected from the group consisting of Trp or D-Trp; R.sub.4 is selected from the group consisting of Thr or Des R.sub.4 ; R.sub.5 is selected from the group consisting of Ser, D-Ser, Phe, X or Des R.sub.5 ; and X is selected from the group consisting of Phe, para-halogenated Phe and para-methoxylated Phe. Provided that at least one X is either para-halogenated Phe or para-methoxylated Phe.

Peptides with para-substituted phenylalanine

Peptides having thermoregulative properties when administered to animals. The peptides are identified by the structure:

Peptides having analgesic and thermoregulative properties

The present invention relates to peptides having dissociated biological activity in respect to the inhibition of growth hormone, insulin, and glucagon secretion. The peptides are analogs of somatostatin.

Somatostatin analogs with dissociated biological activities

The present invention relates to peptides which possess biological activity in respect to the inhibition of growth hormone, insulin secretion and glucagon secretion are provided. The peptides have fewer amino acid components than somatostatin and some of the peptides have dissociated activity.

Growing community of inventors

Del Mar, CA, United States of America

Marvin R Brown