Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Oxytocin; vasopressin; related peptides
Patent
1992-09-23
1995-10-17
Warden, Jill
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Oxytocin; vasopressin; related peptides
530317, 530328, C07K 716
Patent
active
054592364
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new vasotocin derivatives, more specifically such vasotocin derivatives as differ from the native hormone in that the vasotocin (VT) structure has been modified at positions 1, 4, 8 and optionally 2.
The new VT derivatives are vasoactive, more particularly by specifically raising the blood pressure, and in some cases have a considerably prolonged effect.
BACKGROUND
The peptide hormone vasopressin, produced by the posterior lobe of the pituitary, mainly has two functions, that is the hormone has both an antidiuretic effect (reduced excretion of urine) and a contracting effect on smooth muscles in the vascular wall, the latter effect causing a blood pressure increase and a reduced tendency to bleeding. In clinical use, vasopressin thus has a non-specific effect of short duration.
Today, there is on the market a vasopressin analog having a prolonged effect, namely lysine-vasopressin extended in the N-terminal by three amino acid residues. This vasopressin analog acts as a so-called prohormone or hormonogen, i.e. it increases the duration of the vasopressin effect. The extended vasopressin analog has in itself a very small pharmacological effect which does not occur until the extra N-terminal amino acid residues are cleaved by enzymatic hydrolysis and free lysine-vasopressin is formed. Besides the prolonged effect, such a prohormone is advantageous in that the risk of overdosage is minimized by the limited enzyme capacity of the organism determining the plasma levels of the liberated vasopressin. In this manner, it is possible to avoid excessively high plasma levels of vasopressin possibly leading to abnormally increased blood pressure which may harm the patient. The above-mentioned vasopressin analog however suffers from major drawbacks by having low potency and, like vasopressin, being non-specific.
There is a need for vasoconstrictive substances for use as bleeding inhibitors and in so-called orthostatic hypotension, i.e. conditions of blood pressure drop following changes of body position. These agents should specifically increase blood pressure, thus having a low antidiuretic effect in order to avoid water intoxication in patients subjected to long-term treatment. Also, it is advantageous if they exhibit an effect of long duration.
Recently, we have filed (on Oct. 7, 1987) a Swedish patent application SE 8703855-0 (corresponding to PCT/SE88/00509) comprising vasotocin derivatives having specific blood pressure increasing activity. The vasotocin derivatives according to the present invention differ structurally from the vasotocin derivatives according to said prior Swedish patent application mainly in that they have a further modification at position 4 of the vasotocin structure, i.e. they have homoglutamine or homocitrulline at position 4.
DESCRIPTION OF THE INVENTION
The present new vasoactive vasotocin derivatives specifically increase blood pressure, i.e. they are pressor-specific, meaning a high ratio of blood pressure to antidiuretic activity. In particular the antidiuretic effect (reduced excretion of urine) of the parent molecule is eliminated. Furthermore they have a considerably prolonged effect in some cases. The compounds according to the invention are intended to be used in a pharmaceutical composition for inhibiting bleeding and in conditions of blood pressure drop following changes of body position, so-called orthostatic hypotension, and also as general blood pressure increasing agents. The VT derivatives according to the invention are of the formula (SEQ ID NO: 1). ##STR4## wherein Hmp=a 2-hydroxy-3-mercaptopropionic acid residue, ##STR5## Z=phenylalanine (Phe) or tyrosine (Tyr) Y=homoglutamine (Hgn) or homocitrulline (Hci) ##STR6## Q=H or from 1 to 3 amino acid residues of the same or different natural or unnatural L- or D-amino acids, and n is 1, 2 or 3.
The VT derivatives according to the invention can be presented in the form of pharmaceutical compositions in which at least one VT derivative according to the invention is included as active ingredie
REFERENCES:
Manning et al, The Pituitary, eds. C. Beardwell & G. Robinson, Butterworths, Kent England, pp. 265-296, (1981).
Hruky et al, The Peptides, vol. 8, pp. 77-207, (1987).
Melin et al, CA 108; 198503(f); [European J. Pharmacol. vol. 148(1); pp. 93-99, (1988)].
Br. J. Pharmac., vol. 67, 1979 G. W. Bisset et al.: "Hydroxy Analogues of oxytocin and of lysinevasopressin", see pp. 575-585.
Endocrinology, vol. 112, No. 1, 1983 Dean W. Cheesman et al.: "Anovulatory Effect of Synthetic Analogs of Arginine Vasotocin in the Rat", see pp. 269-276.
Aurell Carl-Johan
Melin Per
Nilsson Anders
Trojnar Jerzy
Ferring AB
Warden Jill
Wessendorf T. D.
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