Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Patent
1995-05-31
1998-07-28
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
530330, 530334, 530342, 514 9, 514 11, 514 17, C07K 700
Patent
active
057864470
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of international application PCT/SE95/00462, having an international filing date of Apr. 27,1995, and claiming priority to national application 94 01 596-3, filed in Sweden on May 6, 1994.
THE FIELD OF THE INVENTION
This invention is related to a new class of opioid peptide analogs with mixed .mu. agonist/.delta. antagonist properties as well as to their synthesis and their use as analgesic compounds.
BACKGROUND
The results of a recent study by E. E. Abdelhamid et al., J. Pharmacol. Exp. Ther. 258, 299-303 (1991), indicated that concurrent chronic administration of morphine and the non-peptide .delta. antagonist naltrindole attenuated the development of morphine tolerance and dependence. This important observation suggested that a mixed .mu. agonist/.delta. antagonist may be therapeutically useful as analgesic with low propensity to produce tolerance and dependence. Thus, for therapeutic applications the availability of such a single compound with mixed .mu. agonist/.delta. antagonist properties would be preferable to a combination of a .mu.-agonist (e.g. morphine) and a .delta. antagonist, i.e. a mixture of two compounds.
The first known mixed .mu. agonist/.delta. antagonist was the tetrapeptide amide H-Tyr-Tic-Phe-Phe-NH.sub.2 (TIPP-NH.sub.2 ; Tic=1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) described by P. W. Schiller et al. Proc. Natl. Acad. Sd. USA 89, 11871-11875 (1992). Whereas TIPP-NH.sub.2 has a strong .delta. antagonist component and a relatively weaker .mu. agonist component, its analogs containing a Dmt (2',6'-dimethyltyrosine) residue in place of Tyr.sup.1 show potent .mu. agonist and very potent .delta. antagonist opioid effects.
Prior art
Cyclic .beta.-casomorphin analogs with mixed .mu. agonist/.delta. antagonist properties have recently been disclosed by R. Schmidt et al. at the 13th American Peptide Symposium, Edmonton, Canada, Jun. 20-25, 1993, and at the 3rd International Symposium on .beta.-Casomorphins and Related Peptides, Skovde, Sweden, Jul. 15, 1993. These compounds show a strong .mu. agonist component but a relatively weak .delta. antagonist component. Thus the problem with the compounds known from prior art is that they do not show both a strong .mu. agonist activity and a strong .delta. antagonist activity.
THE INVENTION
It has now unexpectedly been found that the compounds of the following formula I have very potent .mu. agonist potency and very potent .delta. antagonist potency.
The compounds according to the present invention have the formula I ##STR2## wherein R.sub.1 is H, CH.sub.3 (CH.sub.2).sub.n --wherein n=0-12--, preferably n=0-5, ##STR3## R.sub.3 and R.sub.4 respectively are both H or are both C.sub.1 -C.sub.6 alkyl groups, preferably a C.sub.1 -C.sub.4 alkyl group; -C.sub.4 alkyl group; -C.sub.4 alkyl group; -C.sub.4 alkyl group; with the exceptions of compounds wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are all H, and the number (n) of methylene groups in the 2-position side chain is 2, 3 or 4.
Especially preferred compounds according to the invention are those wherein R.sub.3 and R.sub.4 are CH.sub.3. Introduction of methyl substituents at the 2'-and 6'positions of the Tyr.sup.1 aromatic ring drastically increases both .mu. agonist potency and .delta. antagonist potency.
Preferred compounds according to the invention are compounds of the ##STR4## R.sub.2 is hydrogen; R.sub.3 and R.sub.4 are each a CH.sub.3 group;
The most preferred compounds known at present are the compounds according to Examples 3 and 10.
SYNTHESIS
Melting points were determined on a micro hot plate according to BOETIUS and are uncorrected. Optical rotations were measured with a JASCO DIP-370 digital polarimeter. Boc-amino acids were purchased from Bachem Bioscience. Solvents for the synthesis were of analytical grade and were used without further purification with the exception of DMF, which was distilled from ninhydrin and stored under n.sub.2. TLC was performed on prec
REFERENCES:
patent: 4707468 (1987-11-01), Yoshino et al.
Derwent's abstract, No. 90-42476/06, week 906, Abstract of SU 1095-587-A (As Latv. Org. Synthesis) (30 Aug. 1989).
Abelhamid et al., "Selective Blockage of Delta Opioid Receptors Prevents the Development of Morphine Tolerance and Dependance in Mice," J. Pharmacol. Exp. Ther. 258: 299-303 (1991).
Schiller et al., "Differential Stereochemical Requirements of .mu. vs. .delta. Opioid Receptors for Ligand Binding and Signal Transduction: Development of a Class of Potent and Highly .delta.-Selective Peptide Antagonists," Proc. Natl. Acad. Sci. USA 89:11871-11875 (1992).
Schiller et al., "Conformationally Restricted Deltorphin Analogues," J. Med. Chem. 35: 3956-3961 (1992).
Schmidt. et al., J. Med. Chem., 37, 1136-1144, 1994.
Schmidt et al., Int. J. Peptide Protein Res., 37, 502-507, 1991.
STN Fastnotes from STN International.
Schiller Peter
Schmidt Ralf
Astra AB
Delacroix-Muirheid C.
Sanzo Michael A.
Tsang Cecilia J.
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