Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-09-07
1999-02-16
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 11, 514 17, 530317, 530318, 530323, 530330, A61K 3808, A61K 3812, C07K 700
Patent
active
058720979
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE93/00986 Nov. 8, 1993.
FIELD OF THE INVENTION
The invention relates to new oligopeptides SEQ. ID NOS. 1, 2, and 3 with opioid receptor affinity. The peptides can be straight or cyclic pentapeptides with a primary sequence backbone Tyr-X-Phe-Leu-Z. X and Z denote amino acids or amino acid derivatives and/or analogs. X and Z can be covalently coupled to provide a heterocyclic structure. Z is chosen among Cys, Glu, Gln or derivatives of Glu and Gln. X is chosen among amino acids or amino acid analogs such as Ser, Pro, Gly, D-Ala, D- or L-2,4-diaminobutyric acid, trans-(4-aminomethyl)-cyclohexan carboxylic acid (AMCA), Cys or derivatives thereof.
The invention is also directed to pharmaceutical preparations containing the new oligopeptides, which are potentially useful as analgesics for alleviating pain, for increasing the comfort for individuals suffering from extraordinary stress or shock, for reducing depression, and for the possible treatment of individuals addicted to opiates.
BACKGROUND OF THE INVENTION
The physicians treating growth hormone deficient (GHD) patients with human growth hormone have frequently reported that patients experience an increased quality of life in comparison with a control group not subjected to the treatment. Statistically significant differences were found between the groups regarding social isolation, physical mobility, sleep and emotional status (see Acta Paed Scand (Suppl), v356, p55-59, 1989, S Bjork et al. and Acta Paed Scand (Suppl), v356, p70-72, 1989, G A McCauley) In clinical treatment with human growth hormone some secondary effects on the central nervous system (CNS) have been observed. It has been suggested that opioid active peptide fragments released from growth hormone may reach the CNS if the human plasma contains proteolytic activity for releasing them. If such fragments can pass through the blood-brain barrier, they may affect the CNS. These previous studies indicate that human growth hormone affects the CNS and suggests that enzymatically released fragments may interfere with opioid receptors.
A number of studies have shown that enzymatically treated preparations of proteins can include peptides with opioid activity such as .beta.-casomorphin, cytochrophins and hemomorphins. .beta.-casomorphin originates from degraded beta-casein peptone and is previously disclosed in Physiol Chem, v360, p 1211-16, 1979, V Brandl et al.; Pharmacol Sci, v4, p193, 1979, V Brantl et al.; Eur J Pharmacol, v106, p213-214, 1984, V Brantl et al. and J Clin Endocrinol Metab, v68, p283-9, 1989, F Nyberg et al.
It has also been shown that enzymatically derived fragments of mitochondrial cytochrome b contain cytochrophins, another opioid peptide (see Eur J Pharmacol, v111, p293, 1985, V Brantl et al). For a reference of hemomorphins see Eur J Pharmacol, 125, p 309-10,1986, V Brantl et al. The opioid activity of these peptides were confirmed by testing their inhibition of the electrically induced contractions of the guinea-pig ileum myentric plexus longitudinal muscle preparation (GPI-assay) as well as by receptor assay.
Certain cyclic oligopeptides with opioid receptor activity have previously been disclosed by J De Maio et al. in Proc. Natl. Acad. Sci., Vol. 77(12), 1980, p 7162-6. This article discloses a number of prepared cyclic enkephalin analogs. Cyclic oligopeptides with opioid receptor affinity are also disclosed in J Med Chem, Vol. 35, 1992, p 3956-3961, P Schiller et al. U.S. Pat. No. 4,254,024 (J. Stewart et al.) discloses a class of tetrapeptides demonstrated to have opiate activity with a guinea pig ileum strip test having the general formula H-Tyr-X-Y-Z. Another reference that discloses opioid receptor binding straight tetrapeptides is European patent application EP 350 221.
In a previous study, two different peptidases were investigated for their ability to release fragments of human growth hormone, which may interfere with opioid receptors. The enzymes were a commercially available trypsin and an endopeptidase partially purified f
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Fholenhag Karin Ingeborg
Fryklund Linda
Larsson Bo Christer
Lundin Ronny
Nyberg Fred Jarl
Celsa Bennett
Pharmacia & Upjohn Aktiebolag
Tsang Cecilia J.
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