Linear somatostatin analogs

Linear peptide analogs of somatostatin having the formula: ##STR1## As an example, D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr is covered by the above formula (i.e., R.sub.1 is H, R.sub.2 is H, A.sup.1 is D-Phe, A.sup.2 is Phe, A.sup.3 is Phe, A.sup.6 is Thr, A.sup.7 is Phe, A.sup.8 is Thr, and R.sub.3 is NH.sub.2).

BACKGROUND OF THE INVENTION 
This invention relates to therapeutic peptides. 
A number of somatostatin analogs exhibiting Growth 
Hormone-releasing-inhibiting activity have been described in the 
literature, including analogs containing fewer than the naturally 
occurring fourteen amino acids. For example, Coy et al. U.S. Pat. No. 
4,485,101, hereby incorporated by reference, describes dodecapeptides 
having an N-terminal acetyl group, a C-terminal NH.sub.2, D-Trp at 
position 6, and p-Cl-Phe at position 4. (Herein, when no designation of 
configuration is given, the L-isomer is intended.) 
Abbreviations: Nle=norleucine, Nal-naphthylalanine 
SUMMARY OF THE INVENTION 
In general, the invention features a linear somatostatin analog of the 
formula: 
##STR2## 
wherein A.sup.1 is a D- or L-isomer of any of Ala, pyridyl-Ala, Leu, Ile, 
Val, Met, Nle, Thr, Ser, Trp, .beta.-Nal Phe, o-X-Phe (wherein 
X.dbd.CH.sub.3, Cl, Br, F, OH, OCH.sub.3, NO.sub.2), p-X-Phe (wherein 
X.dbd.CH.sub.3, Cl, Br, F, OH, OCH.sub.3, NO.sub.2), 2,4-dichloro-Phe, 
pentafluoro-Phe; 
A.sup.2 is any of Ala, pyridyl-Ala, Leu, Ile, Val, Met, Nle, Trp, 
.beta.-Nal Phe, o-X-Phe (wherein X.dbd.CH.sub.3, Cl, Br, F, OH, OCH.sub.3, 
NO.sub.2), p-X-Phe (wherein X.dbd.CH.sub.3, Cl, Br, F, OH, OCH.sub.3, 
NO.sub.2), 2,4-dichloro-Phe, or pentafluoro-Phe; 
A.sup.3 is any of Ala, pyridyl-Ala, Leu, Ile, Val, Met, Nle, Trp, Tyr, 
.beta.-Nal Phe , o-X-Phe (wherein X.dbd.CH.sub.3, Cl, Br, F, OH, 
OCH.sub.3, NO.sub.2), p-X-Phe (wherein X.dbd.CH.sub.3, Cl, Br, F, OH, 
OCH.sub.3, NO.sub.2), 2,4-dichloro-Phe, or pentafluoro-Phe; 
A.sup.6 is any of Ala, pyridyl-Ala, Leu, Ile, Val, Lys, Met, Nle, Thr, Ser, 
Trp, .beta.-Nal, o-X-Phe (wherein X.dbd.CH.sub.3, Cl, Br, F, OH, 
OCH.sub.3, NO.sub.2), p-X-Phe (wherein X.dbd.CH.sub.3, Cl, Br, F, OH, 
OCH.sub.3, NO.sub.2), 2,4-dichloro-Phe, or pentafluoro-Phe; 
A.sup.7 is any of Ala, pyridyl-Ala, Leu, Ile, Val, Met, Nle, Trp, 
.beta.-Nal Phe , o-X-Phe (wherein X.dbd.CH.sub.3, Cl, OH, OCH.sub.3, 
NO.sub.2), p-X-Phe (wherein X.dbd.CH.sub.3, Cl, Br, F, OH, OCH.sub.3, 
NO.sub.2), 2,4-dichloro-Phe, or pentafluoro-Phe; 
A.sup.8 is a D- or L-isomer of any of Ala, pyridyl-Ala, Leu, Ile, Ser, Thr, 
Val, Met, Nle, Trp, .beta.-Nal Phe, o-X-Phe (wherein X.dbd.CH.sub.3, Cl, 
Br, F, OH, OCH.sub.3, NO.sub.2), p-X-Phe (wherein X.dbd.CH.sub.3, Cl, Br, 
F, OH, OCH.sub.3, NO.sub.2), 2,4-dichloro-Phe, or pentafluoro-Phe; 
each R.sub.1 and R.sub.2, independently, is H, lower (1-5 carbon atoms) 
acyl, or lower alkyl; and R.sub.3 is OH, NH.sub.2, or lower alkyl; 
provided that at least one of A.sup.1 and A.sup.2 and at least one of 
A.sup.7 and A.sup.8 aromatic amino acid; and further provided that 
A.sup.1, A.sup.2, A.sup.7 and A.sup.8 cannot all be aromatic amino acids 
or a pharmaceutically acceptable salt thereof. 
In the formula recited above and in the claims, A.sup.1 stands for an amino 
acid residue of .dbd.N--CH(R)--C.dbd.O-- and each of A.sup.2 through 
A.sup.8 stands for --NH--CH(R)--C.dbd.O--, where R is the identifying 
group of an amino acid, e.g., R is --CH.sub.3 for Ala. 
Preferably, of A.sup.1 and A.sup.2, only one is an aromatic amino acid; and 
of A.sup.7 and A.sup.8, only one is an aromatic amino acid. 
In preferred embodiments A.sup.1 is a D-isomer of any of Trp, .beta.-Nal, 
o-X-Phe (wherein X.dbd.CH.sub.3 or OCH.sub.3), p-X-Phe (wherein 
X.dbd.CH.sub.3 or OCH.sub.3) and A.sup.8 is a D- or L-isomer of any of 
Ala, pyridyl-Ala, Leu, Ile, Ser, Thr, Val, Met, Nle, o-X-Phe (wherein 
X.dbd.Cl, Br, F, OH, NO.sub.2), p-X-Phe (wherein X.dbd.Cl, Br, F, OH, 
NO.sub.2), 2,4-dichloro-Phe, or pentafluoro-Phe. 
In other preferred embodiments A.sup.1 is a D-isomer of any of o-X-Phe 
(wherein X.dbd.H, Cl, Br, F, OH, or NO.sub.2), p-X-Phe (wherein X.dbd.H, 
Cl, Br, F, OH, or NO.sub.2), 2,4-dichloro-Phe, or pentafluoro-Phe; and 
A.sup.8 is a D- or L-isomer of any of Ala, pyridyl-Ala, Leu, Ile, Thr, 
Val, Met, Nle, Trp, .beta.-Nal, o-X-Phe (wherein X.dbd.CH.sub.3 or 
OCH.sub.3), or p-X-Phe (wherein X.dbd.CH.sub.3 or OCH.sub.3). 
In other preferred embodiments A.sup.8 is a D- or L-isomer of any of Thr, 
Trp, .beta.-Nal, o-X-Phe (wherein X.dbd.CH.sub.3 or OCH.sub.3), or p-X-Phe 
(wherein X.dbd.CH.sub.3 or OCH.sub.3); and A.sub.1 is Phe or a D-isomer of 
any of Ala, pyridyl-Ala, Leu, Ile, Val, Met, Nle, o-X-Phe (wherein 
X.dbd.H, Cl, Br, F, OH, NO.sub.2), p-X-Phe (wherein x.dbd.H, Cl, Br, F, 
OH, NO.sub.2), 2,4-dichloro-Phe, or pentafluoro-Phe. 
In other preferred embodiments A.sup.8 is a D- or L-isomer of any of Ser, 
Thr, o-X-Phe (wherein X.dbd.Cl, Br, F, OH, or NO.sub.2), p-X-Phe (wherein 
X.dbd.Cl, Br, F, OH, or NO.sub.2), 2,4-dichloro-Phe, or pentafluoro-Phe; 
and A.sup.1 is a D-isomer of any of Ala, pyridyl-Ala, Leu, Ile, Val, Met, 
Nle, Trp, .beta.-Nal, o-X-Phe (wherein X.dbd.CH.sub.3 or OCH.sub.3), or 
p-X-Phe (wherein X.dbd.CH.sub.3 or OCH.sub.3). 
More preferably, A.sup.1 .dbd..beta.-D-Nal or D-Phe; A.sup.2 .dbd.Ala, Phe 
or p-chloro-Phe; A.sup.3 .dbd.Tyr or Phe; A.sup.6 .dbd.Val, Lys or Thr; 
A.sup.7 .dbd.Ala or Phe; A.sup.8 .dbd.Thr or D-.beta.-Nal. While a 
D-isomer is preferred as the C-terminal residue (which is well known in 
the art to confer stability on the peptides), analogs with an L-isomer at 
that position are also within the invention. Similarly, the N-terminal 
residue can either be of D-or L- configuration. 
Preferred compounds of the invention include 
D-phe-p-chloro-phe-Tyr-D-Trp-Lys-Thr-phe-Thr-NH.sub.2 ; D-Phe-p-NO.sub.2 
-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH.sub.2 ; 
D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH.sub.2 ; 
D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH.sub.2 ; 
D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH.sub.2 ; 
D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH.sub.2 ; and 
D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-B-D-Nal-NH.sub.2. 
In other preferred embodiments, a therapeutically effective amount of the 
therapeutic compound and a pharmaceutically acceptable carrier substance, 
e.g. magnesium carbonate, lactose, or a phospholipid with which the 
therapeutic compound can form a micelle, together form a therapeutic 
composition, e.g. a pill, tablet, capsule, or liquid for oral 
administration to a human patient, a spreadable cream, gel, lotion, or 
ointment to be applied topically or to be iontorphoretially forced through 
the skin of a human patient in need of the compound, a liquid capable of 
being administered nasally as drops or spray, or a liquid capable of 
intravenous, parenteral, subcutaneous, or intraperitoneal administration. 
The pill, tablet or capsule can be coated with a substance capable of 
protecting the composition from the gastric acid in the patient's stomach 
for a period of time sufficient to allow the composition to pass 
undisintegrated into the patient's small intestine. The therapeutic 
composition can also be in the form of a biodegradable or nonbiodegradable 
sustained release formulation for intramuscular administration. For 
maximum efficacy, zero order release is desired, and can be obtained using 
an implantable or external pump, e.g., INFUSOID.sup.TM pump, to administer 
the therapeutic composition. 
The compounds of the invention are active in inhibiting the secretion of 
growth hormone, somatomedins (e.g., IGF-1), insulin, glucagon, and other 
autoparacrine growth factors or pancreatic growth factors. The compounds 
of the invention are acyclic and, therefore, stable and resistant to 
oxidation. In addition, the acyclic nature of the peptide facilitates 
synthesis and purification, improving efficiency and reducing 
manufacturing costs. 
Other features and advantages of the invention will be apparent from the 
following description of the preferred embodiments thereof, and from the 
claims.

STRUCTURE 
The compounds of the invention have the general formula recited in the 
Summary of the Invention, above. They are all octapeptide analogs of 
somatostatin which have D-Trp at the fourth position and Lys at the fifth 
position. An octapeptide of this invention contains at least an aromatic 
amino acid at position A.sup.1 or A.sup.8 and at least an aromatic amino 
acid at position A.sup.2 or A.sup.7, but cannot contain an aromatic amino 
acid at each of A.sup.1, A.sup.2, A.sup.7 and A.sup.8. In other words, 
while at least one aromatic acid must be present at either terminus, 
A.sup.1, A.sup.2, A.sup.7 and A.sup.8 cannot all be aromatic amino acids. 
The compounds can be provided in the form of pharmaceutically acceptable 
salts. Examples of preferred salts are those with therapeutically 
acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, 
ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluenesulfonic, 
or pamoic acid, as well as polymeric acids such as tannic acid or 
carboxymethyl cellulose, and salts with inorganic acids such as the 
hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric 
acid. 
Synthesis 
The synthesis of one therapeutic peptide follows. Other peptides can be 
prepared by making appropriate modifications, within the ability of 
someone of ordinary skill in this field, of the following synthetic 
method. 
The first step in the preparation of the peptide 
EQU D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH.sub.2 
is the preparation of the intermediate: 
Boc-D-Phe-Phe-Phe-D-Trp-N-benzyloxycarbonyl-Lys-O-benzyl-Thr-Phe-O-benzyl-T 
hr-benzhydrylamine resin, as follows. 
Benzhydrylamine-polystyrene resin (Advanced ChemTech, Inc.) (1.2 g, 0.5 
mmole) in the chloride ion form is placed in the reaction vessel of an 
Advanced ChemTech peptide synthesizer programmed to perform the following 
reaction cycle: 
(a) methylene chloride; 
(b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 25 
min each); 
(c) methylene chloride; 
(d) ethanol; 
(e) methylene chloride; and 
(f) 10% triethylamine in chloroform. 
The neutralized resin was stirred with Boc-O-benzyl-threonine and 
diisopropylcarbodiimide (1.5 mmole each) in methylene chloride for 1 hr 
and the resulting amino acid resin is then cycled through steps (a) to (f) 
in the above wash program. The following amino acids (1.5 mmole) are then 
coupled successively by the same procedure: 
Boc-Phe, Boc-O-benzyl-Thr, Boc-N-benzyloxycarbonyl-lysine, Boc-D-Trp, 
Boc-Phe, and Boc-Phe and Boc-D-Phe. After washing and drying, the 
completed resin weighed 1.70 g. 
The resin (1.70 g, 0.5 mmole) is then mixed with cresol (5 ml), 
dithiothreitol (100 mg) and anhydrous hydrogen fluoride (35 ml) at 
0.degree. C. and stirred for 45 min. Excess hydrogen fluoride is 
evaporated rapidly under a stream of dry nitrogen, and free peptide 
precipitated and washed with ether. The crude peptide is then dissolved in 
a minimum volume of 50% acetic acid and eluted on a column (2.5.times.100 
cm) of SEPHADEX G-25 using the same solvent. Fractions containing a major 
component by UV absorption and thin layer chromatography are then pooled, 
evaporated to a small volume and applied to a column (2.5.times.50 cm) of 
VYDAC octadecylsilane silica (10-15 .mu.M). 
The column was eluted with a linear gradient of 10-45% acetonitrile in 0.1% 
trifluoroacetic acid in water. Fractions are examined by thin layer 
chromatography and analytical high performance liquid chromatography and 
pooled to give maximum purity. Repeated lyophilization of the solution 
from water gives 65 mg of the product as a white, fluffy powder. 
The product was found to be homogeneous by hplc and tlc. Amino acid 
analysis of an acid hydrolysate confirms the composition of the 
octapeptide. 
Other peptides of the invention are prepared in an analogous fashion to 
those described above. 
Effects of Linear Somatostatin Analogs on Growth Hormone Secretion in 
Cultured Rat Pituitary Cell Dispersion 
Octapeptides of the invention are tested for inhibtion of growth 
hormone-releasing-activity using rat pituitary cells, as follows. 
Anterior pituitaries from adult Charles River CD male rats (Wilmington, 
Mass.) weighing 200-250 g and housed under controlled conditions (lights 
on from 0500-1900 h), were dispersed and cultured using aseptic technique 
by modification of previously described methods (Hoefer et al., 1984, Mol. 
Cell. Endocrinol. 35:229; Ben-Jonathan et al., 1983, Methods Enzymol. 
103:249; Heiman et al., 1985, Endocrinology 116:410). Pituitaries were 
removed from decapitated rats, sectioned, and then placed into a 
siliconized, liquid scintillation vial containing 2 ml 0.2% trypsin 
(Worthington Biochemicals, Freehold, N.J.) in sterile-filtered 
Krebs-Ringer bicarbonate buffer supplemented with 1% bovine serum albumin, 
14 mM glucose, modified Eagle medium (MEM) vitamin solution and MEM amino 
acids (Gibco Laboratories, Grand Island, N.Y.) (KRBGA). All glassware was 
siliconized as described by Sayers et al., 1971, Endocrinology 88:1063. 
The fragments were incubated in a water bath for 35 min at 37.degree. C. 
with agitation. The vial contents then were poured into a scintillation 
vial containing 2 ml 0.1% DNase (Sigma Chemical Co., St. Louis, Mo.) in 
KRBGA and incubated for 2 min at 37.degree. C. with agitation. After 
incubation the tissue was decanted back into the centrifuge tube and 
allowed to settle. Medium was discarded, and pituitary sections were 
washed 3 times with 1 ml fresh KRBGA. The cells were then dispersed by 
gently drawing the fragments into and expelling them out of a siliconized, 
fire-polished Pasteur pipette in 2 ml 0.05% LBI (lima beam trypsin 
inhibitor, Worthington Biochemicals). Dispersed cells were filtered 
through a 630 .mu.m diameter Nylon mesh (Tetko, Elmsford, N.Y.) into a 
fresh 15 ml centrifuge tube and harvested by centrifugation at 100.times.g 
for 1 min. The final speed was attained gradually through a centrifugation 
period of 17 min. 
After centrifugation, medium was discarded and the pelleted cells were 
resuspended in fresh LBI (2 ml) with a Pasteur pipette. The dispersed 
cells were then diluted with approximately 15 ml sterile-filtered 
Dulbecco's modified Eagle medium (GIBCO), which was supplemented with 2.5% 
fetal calf serum (GIBCO), 3% horse serum (GIBCO), 10% fresh rat serum 
(stored on ice for no longer than 1 h) from the pituitary donors, 1% MEM 
nonessential amino acids (GIBCO), gentamycin (10 ng/ml; Sigma) and 
nyatatin (10,000 U/ml; GIBCO). The cells were poured into a 50 ml 
round-bottomed glass extraction flask with a large diameter opening and 
were counted with a lemacytometer (approximately 2,000,000 cells per 
pituitary) and randomly plated at a density of 200,000 cells per well 
(Co-star cluster 24; Rochester Scientific Co., Rochester, N.Y.). The 
plated cells were maintained in the above Dulbecco's medium in a 
humidified atmosphere of 95% air and 5% CO.sub.2 at 37.degree. C. for 96 
h. 
In preparation for a hormone challenge, the cells were washed 3.times. with 
medium 199 (GIBCO) to remove old medium and U floating cells. Each dose of 
analog (diluted in normal saline in siliconized test tubes) was tested in 
the presence of 1 nM GRF(1-29)NH.sub.2 (growth hormone releasing factor) 
in quadruplicate wells in a total volume of 1 ml medium 199 containing 1% 
BSA (fraction V; Sigma). After 3 h. at 37.degree. C. in an air/carbon 
dioxide atmosphere (95/5%), the medium was removed and stored at 
-20.degree. C. until assayed for hormone content. Growth hormone was 
measured in a conventional radioimmunoassay using anti-growth hormone 
antibody. 
The effect of 9 different peptides on the release of growth hormone in 
cultured rat pituitary cells is shown in FIGS. 1 and 2. The peptides 
DC-25-4 (FIG. 1) and DC-25-24 (FIG. 2) are most active in inhibiting the 
release of growth hormone. Both DC-25-4 and DC-25-24 contain an electron 
withdrawing group near one end of the molecule and an electron donating 
group near the opposite end of the molecule. Peptides DC-23-85 (FIG. 1) 
and DC-25-16 (FIG. 2), which are not within the present invention, show 
essentially no activity. 
Inhibition of I.sup.125 Somatotropin-release-inhibiting Factor (SRIF-14) 
Binding by Linear Somatostatin Analogs 
Crude membrane preparations were obtained from rat pancreas, cerebral 
cortex, or human small cell lung carcinoma (NCI-H69) cells by homogenizing 
(Polytron, setting 6, 15 sec) the tissues or cells in ice-cold 50 mM 
Tris-HCl and centrifuging twice at 39,000.times. g (10 min), with an 
intermediate resuspension in fresh buffer. The final pellets were 
resuspended in 10 mM Tris-HCl for assay. Aliquots of the membrane 
preparation were incubated for 25 min at 30.degree. C. with labeled 
somatotropin-release-inhibiting factor, [.sup.125 I-Tyr.sup.11 ] SRIF-14 
(2000 Ci/mmol, Amersham Corp.), in 50 mM HEPES (pH 7.4) containing bovine 
serum albumin (10 mg/ml; fraction V, Sigma Chem.), MgCl.sub.2 (5mM), 
Trasylol (200 KIU/ml), bacitracin (0.02 mg/ml), and phenylmethylsulphonyl 
fluoride (0.02 mg/ml). The final assay volume was 0.3 ml. The incubations 
were terminated by rapid filtration through Whatman GF/C filters 
(pre-soaked in 0.3% polyethylenimine) under reduced pressure. Each tube 
and filter were then washed three times with 5 ml aliquots of ice-cold 
buffer. Specific binding was defined as the total [.sup.125 I]SRIF-14 
bound minus that bound in the presence of 200 nM unlabelled SRIF-14. 
Table 1 gives results of inhibition of [.sup.125 I]SRIF-14 binding by 
linear peptides of the invention. The concentration of [.sup.125 I]SRIF-14 
was approximately 0.05 nM. (Values in parenthesis indicate the number of 
independent determinations.) The IC.sub.50 (concentration of analog 
resulting is 50% competitive inhibition) in nM values are indicated for 
pancreas, small cell lung carcinoma (SCLC), and brain. The results show 
that analogs DC-25-4 and DC-23-99 are particularly effective in inhibiting 
the binding of I.sup.125 SRIF-14. Peptide DC-23-85, which is not within 
the invention, inhibits the binding of I.sup.125 SRIF-14 only poorly. 
Use 
When administered to mammals, particularly humans, (e.g. orally, topically, 
intravenously, parenterally in a sustained release, biodegradable or 
nonbiodegradable form, nasally, or by suppository), the compounds can be 
effective to inhibit growth hormone release as well as to inhibit 
somatomedins (e.g., IGF-1), insulin, glucagon, other autoparacrine growth 
factors or pancreatic exocrine secretion, and to therapeutically affect 
the central nervous system. 
The compounds can be administered to a mammal, e.g. a human, in the dosages 
used for somatostatin or, because of their greater potency, in smaller 
dosages. The compounds of the invention can be used for the treatment of 
cancer, particularly growth hormone-dependent cancer (e.g., bone, 
cartilage, pancreas (endocrine and exocrine), prostate, or breast), 
acromegaly and related hypersecretory endocrine states, or of bleeding 
ulcers in emergency patients and in those suffering from pancreatitis or 
diarrhea. The compounds can also be used in the management of diabetes and 
to protect the liver of patients suffering from cirrhosis and hepatitis. 
The compounds can also be used to treat Alzheimer's disease, as analgesics 
to treat pain by acting specifically on certain opiate receptors, and as 
gastric cytoprotective compounds for ulcer therapy. The compounds can also 
be used to treat certain types of mushroom poisoning. 
The compounds can also be used to treat diabetes-related retinopathy. The 
anti-cancer activity of the compounds may be related to their ability to 
antagonize cancer-related growth factors such as epidermal growth factor. 
The compounds can be administered to a mammal, e.g., a human, in a dosage 
of 0.01 to 1000 mcg/kg/day, preferably 0.1 to 100 mcg/kg/day. 
Mechanism 
The activity of previously described analogs of somatostatin is dependent 
on the presense of a disulfide linkage between cysteine residues located 
at or near the ends of the peptide, see, e.g., Coy et al. U.S. Pat. No. 
4,485,101, hereby incorporated by reference. The disulfide linkage results 
in a cyclic conformation necessary for activity. 
The inclusion of a disulfide linkage is an undesirable feature in these 
synthetic peptides in that the step favoring synthesis of the disulfide 
linkage imposes a dramatic decrease in the overall yield of the synthesis. 
Furthermore, the disulfide linkages are subject to oxidation and thus 
result in a less stable product. 
The instant invention avoids the use of disulfide linkages and their 
attendant drawbacks. The octapeptides of the instant invention utilize 
non-covalent interactions between the side chains of critically positioned 
constituent amino acid residues to confer a hairpin or quasi-cyclic 
conformation on the peptides. 
The side chains and substituted side chains of the amino acid residues of 
the instant invention are subject to two types of interactions that tend 
to confer the desired tertiary structure on the peptide. The first type of 
interaction occurs when amino acids bearing hydrophobic side chains are 
located at or near both ends of the peptide. Peptides of this structure 
exploit the tendency of hydrophobic moieties to avoid contact with polar 
substances. Interactions between the hydrophobic groups at each end of the 
peptide, favored over interactions between these groups and the polar 
solvents of physiological environments, confer a hairpin or quasi-cyclic 
configuration on the peptide. 
The second type of interaction arises as a result of the interaction of 
electron-donating and electron-withdrawing moieties of amino acids at 
opposite ends of the peptide. The invention features peptides in which an 
amino acid possessing an electron-donating group resides in one end region 
of the peptide while an amino acid possessing an electron-withdrawing 
group resides in the other end region of the peptide. The attraction 
between the electron-donating group, at one end of the peptide, and the 
electron-withdrawing group, at the other end of the peptide, acts to 
confer a hairpin or quasi-cyclic structure on the peptide. Both 
hydrophobic-hydrophobic interactions and electron donor-elctron withdrawer 
interactions may be active in a given peptide. 
Other embodiments are within the following claims. 
TABLE I 
______________________________________ 
TABLE 1 
Inhibition of I.sup.125 SRIF-14 binding by linear 
analogs of somatostatin 
IC.sub.50 (nM) 
Analog Pancreas SCLC Brain 
______________________________________ 
Somatostatin 0.53 (5) 4.2 (5) 0.53 (3) 
BIM-23053/DC-25-4 
2.8 (2) 2.2 (1) 109 
BIM-23052/DC-23-99 
9.4 (1) 1.2 (1) 7.3 (1) 
BIM-23049/DC-23-76 
9.2 (3) 2.1 (1) &gt;10,000 (1) 
BIM-23051/DC-23-89 
34 (2) 15 (1) &gt;10,000 (1) 
BIM-23050/DC-23-85 
264 (1) -- 2,189 (2) 
______________________________________ 
Results are expressed as the concentration in nM of analog that gives 50% 
inhibition of I.sup.125 SRIF-14 binding (IC.sub.50). The numbers in 
parantheses indicate the number of trials. The structure of the analogs is 
as follows: BIM-23049/ 
DC-23-76--.beta.-D-Nal-Ala-Tyr-D-Trp-Lys-Val-Ala-Thr-Nh.sub.2 ; 
BIM-23050/DC-23-85-n-methyl-D-Ala-Tyr-D-Trp-Lys-Val-Phe-NH.sub.2 ; 
BIM-23051/DC-23-89-D-Phe-Ala-Phe-D-Trp-Lys-Thr-Ala-Thr-NH.sub.2 ; 
BIM-23052/DC-23-99-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH.sub.2 ; 
BIM-23053/DC-25-4-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-.beta.-D-Nal-NH.sub.2. 
The structure of SRIF-14 is: 
Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Ser-OH.