Two sets of hormonal peptides are synthesized which are super agonists of the lutenizing hormone releasing hormone (LHRH). Chronic administration results in the inhibition of LHRH which is responsible for stimulating cell growth in the testes. One peptide has the D(dextro)-form of a mono-heterocyclic amino acid in position six (D-3-pyridyl-alanine) while the other peptide has a bi-heterocyclic amino acid in that same position (.beta.-(3-quinolyl)-D-.alpha.-alanine. Both peptides are less metabolically reactive than those in the prior art and yet both peptides are significantly more potent than LHRH itself.

BACKGROUND OF THE INVENTION 
This invention concerns synthetic analogs of the peptide hormone known as 
the leutinizing hormone releasing hormone (LHRH). These analogs have 
biological potency superior to that of the LHRH which exists naturally in 
the hypothalamus of the human brain. 
PROSTATE CANCER 
Carcinoma of the prostate is the second leading cause of cancer-related 
deaths for adult American males who are generally over 55 years of age. 
About 70% of all cases of prostatic neoplasms are hormone-dependent or 
androgen-dependent. Prolactin may be a promoter of prostate growth. The 
medical treatment of prostate cancer emphasizes surgery and the 
therapeutic administration of estrogens and antiangrogens. Surgical 
castration is associated with both psychological and physiological side 
effects which can be extraordinarily serious. The mortality from the 
cardiovascular disease associated with administration of estrogens and 
antiandrogens can be significantly high. 
Other therapeutic treatments of prostatic cancer are not satisfactorily 
effective, and new treatments of great superiority for prostate and other 
hormone related cancers are urgently needed. 
AN EMERGING NEW CHEMOTHERAPY FOR PROSTATE CANCER 
The synthetic analogs of LHRH which can be up to 100 times more potent than 
the natural LHRH have become known as "super agonists" or "super active 
agonists" because of their high potency. The expression "agonist" 
designates the intrinsic activity of a natural hormone. 
Groups of investigators conducting animal studies with these super agonists 
of LHRH observed that the administration caused decreases in the weights 
of the testes, seminal vesicles and the prostate, and decreases in 
testosterone levels and certain receptors. 
In men, two such super agonists, known as D-Trp.sup.6 -LHRH and 
D-Ser(Bu.sup.t).sup.6 des-Gly.sup.10 -NH.sub.2 -LHRH ethylamide were found 
to cause a suppression of Leydig cell function and decreases in serum 
levels of testosterone, dihydrotestosterone and estradiol. These 
reductions were observed after chronic administration of the super 
agonists. 
CLINICAL TRIALS WITH LHRH SUPER AGONISTS IN MEN WITH PROSTATE CANCER 
The observations of the effects of the super agonists of LHRH in the 
diverse animal studies led to clinical trials of these super agonists in 
men with prostate cancer in the hope that the control of prostate cancer 
would be far superior to any existing chemotherapy and particularly to 
surgery. 
Apparently, the first successful palliative treatment of advanced prostatic 
carcinoma in man by super agonists of LHRH was carried out at the Royal 
Victoria Hospital in Montreal by Tollis et al. (Proc. Natl. Acad. Sci., 
USA, 79; 1658-1662 (1982). Both D-Trp.sup.6 -LHRH and 
D-Ser(Bu.sup.t).sup.6 des-Gly.sup.10 -NH.sub.2 -LHRH were administered 
subcutaneously in daily doses of 100 g and 50 g, respectively. In patients 
with urinary obstruction, there was noticeable clinical improvement. In 
patients with more advanced prostatic disease, the pain from bone 
metastases was relieved. 
This collaborative trial demonstrated for the first time that super active 
analogs of LHRH could be beneficial therapeutic agents for prostatic 
cancer, and that such therapy might avoid the psychological impact of 
castration, even unnecessary castration, as well as the cardiovascular, 
hepatic, and mammotropic side effects of estrogens. 
These and numerous other related studies have been reviewed by Schally et 
al. (Proc. Soc. Exp. Biol. Med. 175; 259-281 (1984). 
THE NEED FOR NEWER SUPER AGONISTS OF LHRH FOR TREATMENT OF PROSTATIC CANCER 
Obviously, D-Trp.sup.6 -LHRH and D-Ser(Bu.sup.t).sup.6 des-Gly.sup.10 
-NH.sub.2 -LHRH and related super agonists such as D-Leu.sup.6 LHRH 
ethylamide had all been synthesized solely because such modifications of 
LHRH had higher potencies than that of LHRH itself to release the 
leutenizing hormone. The subsequent years of biological research of the 
super agonists, almost entirely in animals, unexpectedly led to the 
investigations of their possible use to treat prostate cancer. Actually, 
the acute administration of these super agonists to cause release of LH 
and FSH contrasts to the chronic administration which results in 
inhibitory effects. In this endocrinology, the inhibitory effects were 
paradoxical. 
These past super agonists of LHRH had been fortuitously available for the 
prostate cancer studies in animals and in man. There is reason to believe 
that such fortuitous agonists will not be ultimately found to be the 
safest and the most effective agonists to treat prostate cancer in man. 
Such analogs of LHRH are well known to have multiple endocrinological 
activities, and side effects, and chemical differences in stability, and 
enzymic breakdown when injected into man. 
THE DISADVANTAGES OF CERTAIN SUPER AGONISTS OF LHRH 
It is well known in peptide chemistry that certain peptides with a moiety 
(or more than one) of tryptophan may be unstable and discolor on storage 
under diverse conditions. For example, LHRH itself has Trp.sup.3 and the 
super agonist, D-Trp.sup.6 -LHRH, has Trp.sup.3 and D-Trp.sup.6 or the 
super agonist has two moieties of tryptophan which increases sensitivity 
to oxidation and deterioration. For acceptable medical use, a 
chemotherapeutic agent must have necessary chemical stability. Therefore, 
D-Trp.sup.6 -LHRH does not necessarily have the high-level of necessary 
stability which is requisite in chemotherapy. 
D-Ser(Bu.sup.t).sup.6 des-Gly.sup.10 -NH.sub.2 -LHRH and D-Leu.sup.6 
-des-Gly.sup.10 -NH.sub.2 -ethylamide are both analogs of LHRH in which 
glycine has been replaced by a moiety of ethylamide. Such agonists with an 
N-terminal ethylamide moiety had a, fleeting popularity in the field of 
LHRH agonists in the hope that the N-terminal of the peptide would be 
protected against enzymic cleavage and loss of activity. Although this 
aspect of enzymology is theoretically sound, such analogs may show 
unexpected side effects and may not necessarily be safe and effective for 
the treatment of prostate cancer in man over prolonged periods of time. 
SUMMARY OF THE INVENTION 
In this invention, two primary peptides were synthesized which have the 
D(dextro)-form of a monocyclic but heterocyclic amino acid in position 6 
and a bicyclic but heterocyclic amino acid in position 6, respectively. 
The first peptide has a moiety of D-3-pyridyl-alanine in position 6 and 
the second peptide has the moiety of .beta.-(3-quinolyl)-D-.alpha.-alanine 
in position 6. The abbreviation D-3-Pal is used for D-3-pyridylalanine and 
the abbreviation D-3-Qal is used for 
.beta.-(3-quinolyl)-D-.alpha.-alanine. 
Accordingly, these two peptides are: 
I. pyroGlu-His-Trp-Ser-Tyr-D-3-Pal-Leu-Arg-Pro-GlyNH.sub.2 
II. pyroGlu-His-Trp-Ser-Tyr-D-3-Qal-Leu-Arg-Pro-GlyNH.sub.2 
Both of these two new peptides, I, II, when tested biologically, were found 
to be significantly more potent than LHRH itself and, therefore, these two 
new peptides are truly super agonists.