Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Reduced antigenicity – reduced ability to bind complement – or...
Patent
1981-04-29
1983-06-28
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Reduced antigenicity, reduced ability to bind complement, or...
2601125R, 2601125E, A61K 3700, C07C10352
Patent
active
043905277
DESCRIPTION:
BRIEF SUMMARY
The invention deals with new pharmacologically active peptides, in particular, peptides with opiate-like activity, methods for their synthetic manufacture, as well as pharmacologically active peptides manufactured according to these methods.
Pharmacologically active peptides have been known which display, in special biological testing systems, a specific opiate-like activity. They are, in particular, those penta-peptides isolated from the brain by Hughes et al. (Nature 258, 577, 1975): methionine cephalin and the leucine cephalin as well as their longer chain analogues. These known peptides and their synthetic derivatives have the disadvantage in that they lose their pharmacological activity, in this case an opiate-like activity, after treatment in vitro with proteases (for example, Pronase E. Merck) after a short incubation period. On in vivo administration, these peptides are easily attacked and destroyed by proteases naturally present in the body.
During a meeting of the Int. Narcotic Research Conference in June 1979 in North Falmouth, Mass., U.S.A., new peptides, .beta.-casomorphins, have been described which display a novel sequence, which have, based on this sequence, a surprisingly increased stability to the proteases (for example: Pronase E. Merck). These peptides have a strong opiate-like activity in various known testing systems (receptor bonding test and isolated guinea pig intestine.) After injection of 0.35, .mu.mole of .beta.-casomorphin-5 (Tyr-Pro-Phe-Pro-Gly) into the ventricle system of the brain of rats, a strong opiate-like analgesia occurred which reached its maximum effectiveness within 10 minutes and completely disappeared after 60 minutes. This short duration of effectiveness as compared to morphine, with the same analgesia, hints at a possibly complete or partial decomposition of the substance by means of enzymes of the brain.
After parenteral or oral application of the substance, the .beta.-casomorphin-5, which, by the way, has been known up to now as the peptide of the .beta.-casomorphin family with the strongest opiate-like activity, does not show any analgetic effect. The dose in these tests amounted up to 150 mg per kg of body weight of the rats. This disadvantage of the known peptides can be partially or completely attributed to inactivation of the substance in the blood and/or the brain. Incubation tests of the substance with rat brain homogenate or blood plasma showed that the opiate-like activity disappears after a short incubation period of 15 minutes.
It is an object of the invention to provide new pharmacologically active peptides, .beta.-casomorphins, analogues and/or derivatives, which, after incubation (up to 120 minutes) with rat brain homogenate and/or rat brain homogenate supernate and/or blood-plasma (see example of the embodiment) retain their pharmacological activity, for example, opiate-like. Furthermore, it is an object of the present invention to provide pharmacologically active peptides, .beta.-casomorphins, analogues and/or derivatives which, after parenteral (for example, intravenous or subcutaneous injection) and/or oral application, show a pharmacological activity, in particular opiate-like. It is furthermore an object of the invention to make it possible for those skilled in the art, by means of disclosing the amino acid sequence, in particular, the position of the D-amino acid, to manufacture the peptide in any desired amount using customary methods.
These objects are satisfied according to the invention in that the pharmacologically active peptides have the following formula: the amino acid proline. A, B, C . . . can be any amino acid of the stereo chemical L-form. X can be any amino acid of the D-form.
According to a further development of the invention the pharmacologically active peptides have the following formulae: can be any desired D-amino acid.
According to another development of the invention the letters X, A, B, C, D of the listed peptides signify:
According to a particularly advantageous further development of the invention X is replaced by
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Brantl Victor
Henschen Agnes
Lottspeich Friedrich
Teschemacher Hansjorg
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