Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-10-06
1998-09-22
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
562444, 562445, A61K 3805
Patent
active
058114009
DESCRIPTION:
BRIEF SUMMARY
THE FIELD OF THE INVENTION
This invention is related to a novel class of opioid peptide analogs that are .delta. opioid receptor antagonists or mixed .mu. agonist/.delta. antagonists as well as to their synthesis and their use as analgesics 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). However, naltrindole has also quite high .mu. opioid receptor affinity (K.sub.i.sup..mu. =12 nM) in the receptor binding assay and, unlike the compounds according to the present invention, has 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 N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174864) described by R. Cotton, et al. in Eur. J. Pharmacol. 97, 331-332 (1984). In comparison with some of the antagonists described in this patent application, ICI 174864 has much lower .delta. antagonist potency in the MVD assay (200 times less potent).
Peptides containing the H-Tyr-Tic-Aaa sequence (Tic=1,2,3,4-tetra-hydro-isoquinoline-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 Conference (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, Shizuoka, Japan, Nov. 9-13 (1992), at the 22nd European Peptide Symposium Interlaken, Switzerland, Sep. 9-13 (1992), in Proc. Natl. Acad. Sci. USA 89 11871-11875 (1992), and in J. Med. Chem. 36 3182-3187 (1993).
Peptides structurally related to TIPP that are mixed .mu. agonist/.delta. antagonists have recently been disclosed by P. W. Schiller et al. in Proc. Natl. Acad. Sci. USA 89, 11871-11875 (1992) and at the International Narcotics Research Conference (INRC) Meeting in North Falmouth, Mass., USA, Jul. 16-21 (1994). Cyclic .beta.-casomorphin analogs with mixed .mu. agonist/.delta. antagonist properties have recently been disclosed by R. Schmidt et al. in J. Med. Chem. 37, 1136-1144 (1994). On the basis of results obtained by E. E. Abdelhamid et al., J. Pharmacol. Exp. Ther. 258, 299-303 (1991), mixed .mu. agonist/.delta. antagonists are of interest because they are expected to be analgesics with low propensity to produce tolerance and dependence.
The problem underlying the present invention was to find new dipeptide derivatives with .delta. antagonist or mixed .mu. agonist/.delta. antagonist properties that have a low molecular weight and are highly lipophilic. These properties should facilitate passage across the blood-brain barrier.
THE INVENTION
It has now been found that certain novel derivatives of the dipeptide H-Tyr-Tic-OH, as defined by the following formula I, have
high potency as .delta. antagonists
mixed .mu. agonist/.delta. antagonist properties
total lack of .mu. antagonist properties
The novel 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 argininyl;
R.sub.2 is H; CH.sub.3 (CH.sub.2).sub.n --wherein n=0-12; ##STR4## or
--CH.sub.2 CH.dbd.CH.sub.2 ;
R.sub.3, R.sub.4, R.sub.5, 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 are both C.sub.1 -C.sub.6 alkyl; or
R.sub.3, R.sub.5, R.sub.6 are all H and R.sub.4 is F, Cl, Br, OH, NH.sub.2 or NO.sub.2 ;
R.sub.7 is carbonyl or CH.sub.2 ;
R.sub.8 is H or C.sub.1 -C.sub.12 alkyl, or aralkyl wherein alkyl is C.sub.1 -C.sub.12 alkyl;
R.sub.9 is a linear or branched C.sub.1 -C.sub.12 alkyl or aralkyl wherein alkyl is C.sub.1 -C.sub.12 alkyl, or
C.sub.1 -C.sub.12 alkyl linked to a heterocyclic moiety.
Illustrative examples of R.sub.9 are ##STR5## adamantyl--(CH.sub.2).sub
REFERENCES:
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, Letters to the Editor (1988).
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.,"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).
Schmidt et al., "Cyclic .beta.-Casomorphin Analogues with Mixed .mu. Agonist/.delta. Antagonist Properties: Synthesis, Pharmacological Characterization, and Conformational Aspects," J. Med. Chem. 37:1136-1144 (1994).
Abdelhamid et al., "Selective Blockage of Delta Opioid Receptors Prevents the Development of Morphine Tolerance and Dependence in Mice," J. Pharmacol. Exp. Ther. 258:299-303 (1991).
Cotton et al., "ICI 174864: A Highly Selective Antagonist for the Opioid .delta.-Receptor," Eur. J. Pharmacol. 97:331-332 (1984).
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).
Astra AB
Lukton David
Sanzo Michael A.
Tsang Cecilia J.
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