Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-10-02
2002-01-08
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S302000, C530S330000, C530S333000
Reexamination Certificate
active
06337319
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
The present application represents U.S. national stage of internationl application PCT/SE96/01011, with an international filing date of Aug. 14 1996. The international application was published in English under Article
22(2)
of the PCT. It claims priority to Swedish application
9502877-5
filed on Aug. 18, 1995, and to Swedish application
9503924-4
filed on Nov. 7, 1995.
FIELD OF THE INVENTION
The present invention relates to opioid-like peptide compounds. More particularly, it relates to opioid-like peptide compounds that exhibit peripheral analgesic activity and selectivity for the &mgr; subtype of opioid receptors.
BACKGROUND OF THE INVENTION
Many endogenous peptides of mammalian and amphibian origin bind to specific opioid receptors and elicit an analgesic response similar to classic narcotic opiates. Many different types of opioid receptors have been shown to coexist in higher animals. For example, see W. Martin et al.,
J. Pharmacol. Exp. Ther
., 197, p. 517(1975); and J. Lord et al.,
Nature
(
London
) ,257 p. 495(1977). Three different types of opioid receptors have been identified. The first, &dgr;, shows a differentiating affinity for enkephalin-like peptides. The second, &mgr;, shows enhanced selectivity for morphine and other poly-cyclic alkaloids. The third, &kgr;, exhibits equal affinity for either group of the above ligands and preferential affinity for dynorphin. In general, the &mgr;-receptors seem to be more involved with analgesic effects. The &dgr;-receptors appear to deal with behavioral effects, although the &dgr; and the &kgr;-receptors may also mediate analgesia.
Each opioid receptor, when coupled with an opiate, causes a specific biological response unique to that type of receptor. When an opiate activates more than one receptor, the biological response for each receptor is affected, thereby producing side effects. The less specific and selective an opiate may be, the greater the chance of causing increased side effects by the administration of the opiate.
In the prior art, opiates, opioid peptides, and analogs thereof, have either failed to demonstrate, or have demonstrated a limited degree of selectivity for the type of receptor, or receptors, to which they bind.
Opiates can cause serious and potentially fatal side effects. Side effects such as respiratory depression, tolerance, physical dependence capacity, and precipitated withdrawal syndrome are caused by nonspecific interactions with central nervous system receptors. See K. Budd, In
International Encyclopedia of Pharmacology and Therapeutics
; N. E. Williams and H. Wilkinson, Eds., Pergammon: (Oxford), 112, p.51 (1983). Therefore, opioid analgesics acting principally through opioid receptors in the peripheral nervous system would not be expected to cause similar unwanted side effects as those side effects associated with opioid analgesics affecting the central nervous system.
To date, one of the few classes of agents known to exert peripheral analgesic effects are non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, and ketorolac. These agents do not interact with opioid receptors but are known to inhibit cyclooxygenase and attenuate prostaglandin synthesis. These weak analgesics do not have centrally mediated side effects, but they can cause other side effects such as ulcerations of the gastro-intestinal tract.
It was thought that non-polar peptides pass more easily into the central nervous system than polar peptides by traversing the blood-brain barrier. It has been published that TAPP(H-Tyr-D-Ala-Phe-Phe-NH
2
) exhibited antinociceptive properties both peripherally and centrally (P. Schiller et al.,
Proceedings of the
20
th
European Peptide Symposium
, 1988). In contradiction, it has been found by the present inventor that this tetrapeptide does not act centrally even at doses of 100 mg/kg.
It is an object of the invention to provide opioid-like peptide compounds which act peripherally but substantially avoid the unwanted side effects associated with conventional peripherally acting analgesics. It is a further object to provide peptide compounds which bind selectively to the &mgr;-opioid receptor.
SUMMARY OF THE INVENTION
The present invention provides novel peptide compounds which act peripherally and are selective for &mgr;-opioid receptors, the compound represented by formula (1):
and salts, derivatives and analogues thereof
wherein,
R
1
is Tyr or 2′,6′-dimethyltyrosine, or an analog or derivative thereof;
R
2
is D-Ala or D-Arg;
R
3
is Phe(p-F);
R
4
is Phe or Phe(p-F);
X is H or C
1-6
alkyl; and
Y and Z are independently H, aralkyl or C
1-6
alkyl.
In another aspect of the invention, there is provided pharmaceutical compositions comprising a compound of formula (1) in admixture with a pharmaceutically acceptable carrier and/or a second therapeutically active agent.
In a further aspect of the invention, there is provided a method of treating pain comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of formula (1).
In a further aspect of the invention, there is provided the use of a compound of formula (1)for the manufacture of a medicament for treating pain.
REFERENCES:
patent: 5312899 (1994-05-01), Schiller
patent: WO 95/22557 (1995-08-01), None
patent: WO95/22557 (1995-08-01), None
Filler, R ‘Biologically Active Fluorochemicals’, J. of Fluorine Chemistry, vol. 33, pp. 361-375 (1986).*
Bodanszky,Principles of Peptide Synthesis, Berlin:Springer-Verlag (1984).
Budd, “Analgesis Drugs” inInternational Encyclopedia of Pharmacology and Therapeutics, eds. N.E. Williams and H. Wilkinson, Oxford:Pergammon (1983), 51-63.
The Peptides, New York:Adacemic Press (1979).
Lord, et al., “Endogenous Opioid Peptides: Multiple Agonists and Receptors,”Nature 267:495-499 (1977).
Martin, et al., “The Effects of Morphine- and Nalorphine-Like Drugs in the Nondependent and Morphine-Dependent Chronic Spinal Dog,”J. Pharmacol. and Exper. Ther. 197:517-532 (1976).
Schiller, et al., “Insulfated C-Terminal 7-Peptide of Cholecystokinin: A New Ligand of the Opiate Receptor,”Biochem. and Biophys. Res. Comm. 85: 1332-1338 (1978).
Schiller, et al., “New Types of Opioid Peptide Analog Showing High &mgr;-Receptor Selectivity and Preference for Either Central or Peripheral Sites,”Peptides 1988, Proceedings of the 20th European Peptide Symposium, 613-615 (1988).
Silbert, et al., “Analgesic Activity of a Novel Bivalent Opioid Peptide Compared to Morphine Via Different Routes of Administration,”Agents and Actions 33:382-387 (1991).
Siegmund, et al., “A Method for Evaluating Both Non-Narcotic and Narcotic Analgesics,”Proc. Soc. Exp. Biol. Med. 95:729-731 (1957).
Woolfe, et al., “The Evaluation of the Analgesic Action of Pethidine Hydrochloride (Demerol),”J. Pharmacol. and Exp. Ther. 80:300-307 (1944).
International Search Report for Swedish appls 9502877-5 and 9503924-4 (priority appls. of PCT/SE96/01011).
Gupta Anish
Low Christopher S. F.
Sanzo Michael A.
LandOfFree
&mgr;-Selective opioid peptides does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with &mgr;-Selective opioid peptides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and &mgr;-Selective opioid peptides will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2845362