Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-03-26
2002-06-18
Kunz, Gary L. (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C530S300000, C530S350000, C435S069100
Reexamination Certificate
active
06406866
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to opioid receptors from mammalian species and ligands specific for such receptors. Specifically, the invention relates to the isolation of an endogenous peptide ligand specific for a novel mammalian opioid receptor. The invention also relates to the construction of analogues, derivatives and peptide mimetics of this endogenous mammalian opioid receptor ligand. Specifically provided is a mammalian hypothalamus-derived endogenous opioid receptor ligand, synthetic embodiments and analogues thereof. Methods of making and using such ligands, as well as antibodies against and epitopes of this novel opioid receptor ligand are also provided by the invention.
2. Background of the Invention
The use (and abuse) of opiates, archetypally opium and morphine, have been known since antiquity (reviewed in Brownstein, 1993, Proc. Natl. Acad. Sci. USA 90: 5391-5393). Since the nineteenth century, chemical characterization and synthesis of a number of morphine analogues have been achieved in an effort to discover a compound with the analgesic effects of morphine that lacks or is substantially attenuated in its addictive potential. These efforts have proven fruitless to date.
The biology behind the reasons why morphine and morphine-like compounds display both analgesic and addictive properties was first elucidated by the discovery of endogenous morphine-like compounds termed enkephalins (see DiChara & North, 1992, Trends in Pharmacol. Sci. 13: 185-193 for review). Accompanying this finding of an endogenous opiate was the biochemical evidence for a family of related but distinct opiate receptors, each of which displays a unique pharmacological profile of response to opiate agonists and antagonists (see McKnight & Rees, 1991, Neurotransmissions 7: 1-6 for review). To date, four distinct opiate receptors have been described by their pharmacological profiles and anatomical distribution: these comprise the &mgr;, &dgr;, &kgr; and &sgr; receptors (the &sgr; receptor has been determined to be a non-opioid receptor with cross-reactivity to some opioid agonists).
Thus, mammalian opioid receptors are known in the art, and some of these proteins have been isolated biochemically and their corresponding genes have been recently cloned using genetic engineering means.
Kieffer et al., 1992, Proc. Natl. Acad. Sci. USA 89: 12048-12052 disclosed the isolation of a cDNA copy of the mouse &dgr;-opioid receptor by expression cloning.
Evans et al., 1992, Science 258: 1952-1955 disclose the isolation of a cDNA copy of the mouse &dgr;-opioid receptor by expression cloning.
Chen et al., 1993, Molec. Pharmacol. 44: 8-12 disclose the isolation of a cDNA copy of the rat &mgr;-opioid receptor.
Yasuda et al., 1993, Proc. Natl. Acad. Sci. USA 90: 6736-6740 disclose the isolation of a cDNA copy of each of the mouse K- and &dgr;-opioid receptor.
Bzdega et al., 1993, Proc. Natl. Acad. Scd. USA 90: 9305-9309 disclose the isolation and chromosomal location of the &dgr;-opioid receptor in the mouse.
The present inventors have cloned, expressed and functionally characterized a novel mammalian opioid receptor gene, disclosed in co-owned and co-pending U.S. patent application, Ser. No. 08/149,093, filed Nov. 8, 1993, and issued as U.S. Pat. No. 5,658,783 on Aug. 19, 1997 which is hereby incorporated by reference in its entirety. Specifically disclosed therein are nucleic acids encoding the novel mammalian opioid receptor gene, recombinant expression constructs comprising this opioid receptor gene, cells containing such constructs and expressing the novel opioid receptor gene, and methods for making and using such nucleic acids, constructs and cells for opioid detection and novel drug screening. The nucleic acid sequence of the MSOR gene and the deduced amino acid sequence of the cognate receptor protein were also disclosed in this prior application.
In 1991, U.S. pharmaceutical companies spent an estimated $7.9 billion on research and development devoted to identifying new therapeutic agents (Pharmaceutical Manufacturer's Association). The magnitude of this amount is due, in part, to the fact that the hundreds, if not thousands, of chemical compounds must be tested in order to identify a single effective therapeutic agent that does not engender unacceptable levels of undesirable or deleterious side effects. There is an increasing need for economical methods of testing large numbers of chemical compounds to quickly identify those compounds that are likely to be effective in treating disease.
This is of particular importance for psychoactive and psychotropic drugs, due to their pharmacological importance and their potential to greatly benefit or greatly harm human patients treated with such drugs. At present, few such economical systems exist. Conventional screening methods require the use of animal brain slices in binding assays as a first step. This is suboptimal for a number of reasons, including interference in the binding assay by non-specific binding of heterologous (i.e., non-receptor) cell surface proteins expressed by brain cells in such slices; differential binding by cells other than neuronal cells present in the brain slice, such as glial cells or blood cells; and the possibility that putative drug binding behavior in animal brain cells will differ from the binding behavior in human brain cells in subtle but critical ways. For these and other reasons, development of in vitro screening methods for psychotropic drugs has numerous advantages and is a major research goal in the pharmaceutical industry. The ability to synthesize human opioid receptor molecules in vitro would represent one way to provide an efficient and economical means for rational drug design and rapid screening of potentially useful compounds.
A great advantage in efforts for developing novel psychotropic drugs which exert their activity (analgesic and otherwise) aria binding to mammalian opioid receptors would be to identify the endogenous ligand(s) which bind to such receptors. Certain such ligands have been isolated in the prior art, including the peptides comprising the endorphins and enkephalins (see Jaffe and Martin, 1990, “Opioid Analgesics and Antagonists”, in Goodman and Gilman, eds.,
The Pharmacological Basis of Therapeutics,
8th ed. (Pergammon Press, Inc.: New York), Chapter 21, p.485-521). The identification and characterization of additional endogenous ligands would advantageously provide another basis for rational drug design and an appreciation for structural features of such ligands both shared with other opioid receptor ligands and unique for ligands specific for individual receptors or subclasses of receptors.
SUMMARY OF THE INVENTION
This invention provides small, readily-produced peptides that are ligands for a novel mammalian opioid receptor protein having the amino acid sequence identified as SEQ ID Nos.: 5 and 6. Peptides of the invention are characterized as having an amino acid sequence that is the amino acid sequence identified as SEQ ID Nos.: 5 and 6 or a subsequence thereof, amino acid sequence variants of the sequence or subsequence, as well as analogues and derivatives thereof, that are ligands for the novel mammalian opioid receptor protein having the amino acid sequence identified as SEQ ID Nos.: 5 and 6, as well as analogues and derivative thereof.
The peptides of the invention include linear and cyclized peptides, and synthetic analogues and variants thereof. Certain embodiments of such variants include, substitution variants, wherein an amino acid residue at one or more positions in the peptide is replaced with a different amino acid residue (including atypical amino acid residues) from that found in the corresponding position of amino acid sequence of the parent peptide of the invention. In a preferred embodiment, the substituted amino acid is tyrosine. Certain other embodiments of peptide variants of the invention include addition variants, wherein such variant peptides may include up to about a total of 10 additional amino acids, covalently
Bunzow James R.
Civelli Olivier
Grandy David K.
Monsma Frederick James
Nothacker Hans-Peter
Klarquist & Sparkman, LLP
Kunz Gary L.
Landsman Robert S.
Oregon Health & Sciences University
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