Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-08-22
1998-03-31
Huff, Sheela
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 19, 514885, 514886, 530330, 530331, 530302, 530333, 530334, 530335, 530336, 530337, 530338, A61K 3800, C07K 500, C07K 700, C07K 1700
Patent
active
057338817
DESCRIPTION:
BRIEF SUMMARY
THE FIELD OF THE INVENTION
This invention is related to a new class of opioid peptide analogs that are .delta. opioid receptor antagonists as well as to their synthesis and their use as analgesic and immunosuppressive compounds.
BACKGROUND AND PRIOR ART
A known nonpeptide .delta. opioid antagonist is naltrindole, which is described by P. S. Portoghese, et al J. Med. Chem. 31, 281-282 (1988). Naltrindole has similar .delta. antagonist potency as the compounds according to this invention but is much less .delta. selective. Furthermore, naltrindole has also quite high .mu. opioid receptor affinity (K.sub.i.sup..mu. =12 nM) in the receptor binding assay and potent .mu. antagonist properties (K.sub.e =29 nM) in the guinea pig ileum (GPI) assay, cf P. S. Portoghese, J. Med. Chem. 34, 1757-1762 (1991).
Another known .delta.-antagonist is the enkephalin analog (ICI 174864) described by R. Cotton, et al. in Eur. J. Pharmacol. 97, 331-332 (1984). In comparison with the .delta. antagonists described in this patent application, ICI 174864 is much less .delta.-selective (10-300 times less) and has much lower antagonist potency in the MVD assay (40-1000 times less potent).
Peptides containing the H-Tyr-Tic-Aaa-sequence (Tic=1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Aaa=aromatic amino acid residue) at the N-terminus and which are very potent and highly selective .delta. antagonists have recently been disclosed by P. W. Schiller et al. in FASEB J, 6 (No. 4), A1575 (1992), at the International Narcotics Research (INRC) Meetings in Keystone, Colo., Jun. 24-29 (1992) and in Skovde, Sweden, Jul. 10-15 (1993), at the 2nd Japan Symposium on Peptide Chemistry Shi-zuoka, Japan, Nov. 9-13 (1992), at the 22nd European Peptide Symposium, Interlaken, Switzerland, Sep. 13-19 (1992), in Proc. Natl. Acad. Sci. U.S.A. 89, 11871-11875 (1992), and in J. Med. Chem. 36, 3182-3187 (1993).
Thus, the problem underlying the present invention was to find .delta. opioid antagonists both with high .delta. antagonist potency and with high .delta. selectivity.
THE INVENTION
It has now been found that peptides containing the H-Tyr-Tic-dipeptide segment at the N-terminus and a non-aromatic amino acid residue at the 3-position of the peptide sequence, as defined by the following formula I, have
The compounds according to the present invention have the general formula I ##STR2## wherein
R.sub.1 is H; CH.sub.3 (CH.sub.2).sub.n -- wherein n=0-12; ##STR3## --CH.sub.2 --CH.dbd.CH.sub.2 ; or arginine;
R.sub.2 is H; CH.sub.3 (CH.sub.2).sub.n -- wherein n=0-12; CH.sub.3 --; ##STR4## or
--CH.sub.2 --CH.dbd.CH.sub.2 ;
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H; or
R.sub.4 and R.sub.5 are both H and R.sub.3 and R.sub.6 is each a C.sub.1 -C.sub.6 alkyl group; or
R.sub.3, R.sub.5 and R.sub.6 are all H and R.sub.4 is F, Cl, Br, I, OH, NH.sub.2 or NO.sub.2 ;
R.sub.7 is C.dbd.O or CH.sub.2 ;
R.sub.8 is H or a C.sub.1 -C.sub.6 alkyl group;
R.sub.9 is selected from ##STR5## wherein m is 0-12; ##STR6## wherein p is 0-4;
R.sub.10 is OH, NH.sub.2 or ##STR7## wherein
R.sub.11 is H, NO.sub.2, F, Cl, Br or I; q is 0-3;
R.sub.12 is COOH, CONH.sub.2, CH.sub.2 OH, or any additional amino acid or peptide segment; or
R.sub.10 is ##STR8## wherein
R.sub.12 is as defined above.
Preferred compounds of the invention are those compounds wherein
R.sub.1 is selected from H or CH.sub.3 ;
R.sub.2 is selected from H or CH.sub.3 ;
R.sub.3 is selected from H or CH.sub.3 ;
R.sub.4 is H;
R.sub.5 is H;
R.sub.6 is selected from H or CH.sub.3 ;
R.sub.7 is selected from CO or CH.sub.2 ;
R.sub.8 is selected from H or CH.sub.3 ;
R.sub.9 is selected from ##STR9## wherein p=0-4 or ##STR10##
R.sub.10 is selected from ##STR11## wherein R.sub.11 is H, NO.sub.2, F, Cl, Br or I,
q is 1-3, and R.sub.12 is COOH.
Especially preferred compounds of the invention are those compounds wherein
R.sub.1 is selected from H or CH.sub.3 ;
R.sub.2 is selected from H or CH.sub.3 ;
R.sub.3 is selected from CH.sub.3 ;
R.sub.4 is selected from H;
R.sub.5 is selected from H;
R.sub.6 is selected from CH.sub.3
REFERENCES:
Temussi et al, BBRC vol. 198 p. 933, Feb. 1994.
Merck, 11th edition pp. 1006-1007, 1989.
Cotton et al., "ICI 174864: A Highly Selective Antagonist for the Opioid .delta.-Receptor," Eur. J. Pharmacol. 97:331-332 (1984).
Portoghese et al., "Application of the Message-Address Concept in the Design of Highly Potent and Selective Non-Peptide .delta. Opioid Receptor Antagonists," J. Med. Chem. 31:281-282 (1988).
Portoghese, "An Approach to the Design of Receptor-Type-Selective Non-Peptide Antagonists of Peptidergic Receptors: .delta. Opioid Antagonists," J. Med. Chem. 34:1757-1762 (1991).
Schiller et al., "A New Class of Potent and Highly Selective .delta. Opioid Receptor Peptide Antagonists Without .mu. Antagonist Properties," FASEB J. 6:A1575, Abstract No. 3699 (1992).
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). .delta. Opioid Receptor Antagonist with Extraordinary .delta. Selectivity," J. Med. Chem. 36:3182-3187 (1993).
Astra AB
Huff Sheela
Sanzo Michael A.
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