US4416871A
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US
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Inhibition by peptides of tolerance to and physical dependence on morphine
Assignee: United States Department of Health and Human Services
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Filing: 1982-01-11
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Granted: 1983-11-22
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Expires: 2002-01-11
Abstract
Abstract Certain peptides administered during chronic morphine treatment were found to be effective in preventing development of tolerance and physical dependence. Particularly effective are prolyl-leucyl-glycinamide, cyclo(leucylglycine), and the protected peptide N-carbobenzoxy-prolyl-D-leucine, which, injected daily into mice receiving chronic morphine treatment, prevented the development of physical dependency as measured by changes in body temperature and body weight, either during abrupt or naloxone-induced withdrawal. But injection of peptide only on the last day of morphine treatment did not alter the overt signs of withdrawal. Daily injection of peptide was also effective in blocking the development of tolerance to analgesic and hypothermic effects of subsequent challenge doses of morphine. The peptide treatment did not alter the acute effects of morphine on either analgesia or body temperature. No effects on memory were noted, as evaulated in a one-trial passive avoidance task.
Inventors
- 👤 Roderich W. Walter
- 👤 William A. Krivoy
- 👤 Ronald F. Ritzmann
- 👤 Hemendra N. Bhargava
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 09:57
CPC Classifications
C; C07; C07K; C07K5/00; C07K5/04; C07K5/12; A; A61; A61K; A61K38/00; A61K38/04; C07K5/06; C07K5/06139; C07K5/06165; C07K5/08; C07K5/0821; C07K5/0823; C07K5/10; C07K5/1002; C07K5/1005; C07K5/1008
Claims Analysis
Total Claims: 13
Claim 1
Independent Claim
51 words
An analgesic composition comprising morphine and a dipeptide selected from the group consisting of Pro-Leu, D-Pro-D-Leu, D-Pro-Leu, Pro-D-Leu, Pro-Gln, Pro-Ser, Pro-Met, Pro-ΔPhe, and Pro-Tyr, the dipeptide being present in amount sufficient to inhibit the development of tolerance to and physical dependence on the morphine without substantial alteration of its analgesic properties.
Claim 2
Dependent Claim
51 words
An analgesic composition comprising morphine and a dipeptide selected from the group consisting of Pro-Leu, D-Pro-D-Leu, D-Pro-Leu, Pro-D-Leu, Pro-Gln, Pro-Ser, Pro-Met, Pro-ΔPhe, and Pro-Tyr, the dipeptide being present in amount sufficient to inhibit the development of tolerance to and physical dependence on the morphine without substantial alteration of its analgesic properties.
Claim 3
Dependent Claim
30 words
The composition of claim 1 wherein the primary amino function of the dipeptide is protected by the moiety selected from the group consisting of carbobenzoxy, t-butoxycarbonyl, α,α-dimethyl-3,4-dimethoxybenzyloxycarbonyl, triphenylmethyl, and benzyl.
Claim 4
Dependent Claim
46 words
An analgesic composition comprising morphine and a cyclic dipeptide selected from the group consisting of cyclo(Leu-Gly) and cyclo(Pro-Phe), the cyclic peptide being present in amount sufficient to inhibit the development of tolerance to and physical dependence on the morphine without substantial alteration of its analgesic properties.
Claim 5
Dependent Claim
46 words
An analgesic composition comprising morphine and a cyclic dipeptide selected from the group consisting of cyclo(Leu-Gly) and cyclo(Pro-Phe), the cyclic peptide being present in amount sufficient to inhibit the development of tolerance to and physical dependence on the morphine without substantial alteration of its analgesic properties.
Claim 6
Dependent Claim
49 words
An analgesic composition comprising morphine and a tripeptide amide selected from the group consisting of Pro-Leu-Gly-NH 2 and [Glu-Leu-Gly-NH 2 ,] the tripeptide amide being present in amount sufficient to inhibit the development of tolerance to and physical dependence on the morphine without substantial alteration of its analgesic properties.
Claim 7
Dependent Claim
49 words
An analgesic composition comprising morphine and a tripeptide amide selected from the group consisting of Pro-Leu-Gly-NH 2 and [Glu-Leu-Gly-NH 2 ,] the tripeptide amide being present in amount sufficient to inhibit the development of tolerance to and physical dependence on the morphine without substantial alteration of its analgesic properties.
Claim 8
Dependent Claim
30 words
The composition of claim 4 wherein the primary amino function of the tripeptide is protected by the moiety selected from the group consisting of carbobenzoxy, t-butoxycarbonyl, α,α-dimethyl-3,4-dimethoxybenzyloxycarbonyl, triphenylmethyl, and benzyl.
Claim 9
Dependent Claim
48 words
A method of inhibiting the development of tolerance to and physical dependence on morphine in mammals, without substantial alteration of the analgesic effects thereof, comprising the administration thereto, during morphine treatment, from about 0.20 to about 100 mg/kg of at least one of the peptides of claim 1.
Claim 10
Dependent Claim
26 words
The method of claim 6 wherein from about 0.20 to about 100 mg/kg of at least one of the protected peptides of claim 2 is utilized.
Claim 11
Dependent Claim
26 words
The method of claim 6 wherein from about 0.002 to about 100 mg/kg of at least one of the cyclic peptides of claim 3 is utilized.
Claim 12
Dependent Claim
25 words
The method of claim 6 wherein from about 0.02 to about 100 mg/kg of at least one of the peptides of claim 4 is utilized.
Claim 13
Dependent Claim
26 words
The method of claim 6 wherein from about 0.02 to about 100 mg/kg of at least one of the protected peptide-amides of claim 5 is utilized.
References Cited (Backward Citations)
No citation records indexed.
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1986-11-21 | 1987-05-23 | 1987-11-22 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1990-11-21 | 1991-05-23 | 1991-11-22 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1994-11-21 | 1995-05-23 | 1995-11-22 | $7700.00 | Window Closed / Lapsed |