Methods of screening modulators of opioid receptor activity

Details Methods of screening modulators of opioid receptor activity Methods of screening modulators of opioid receptor activity

1995-03-14

2002-08-13

Kunz, Gary L. (Department: 1647)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

C435S007100, C435S069100, C435S070100, C435S071100, C435S071200

Reexamination Certificate

active

06432652

ABSTRACT:

TECHNICAL FIELD
The invention relates to substances involved in vertebrate nervous systems, and in particular to the opioid receptors and receptor-like proteins (also referred to as opioid receptors herein) and activities mediated thereby. Accordingly, the invention concerns recombinant materials useful for the production of opioid receptors, the receptor as a diagnostic tool, therapeutic and diagnostic compositions relevant to the receptor, and methods of using the receptor to screen for drugs that modulate the activity of the receptor.
BACKGROUND ART
The term “opioid” generically refers to all drugs, natural and synthetic, that have morphine-like actions. Formerly, the term “opiate” was used to designate drugs derived from opium, e.g., morphine, codeine, and many semi-synthetic congeners of morphine. After the isolation of peptide compounds with morphine-like actions, the term opioid was introduced to refer generically to all drugs with morphine-like actions. Included among opioids are various peptides that exhibit morphine-like activity, such as endorphins, enkephalins and dynorphins. However, some sources have continued to use the term “opiate” in a generic sense, and in such contexts, opiate and opioid are interchangeable. Additionally, the term opioid has been used to refer to antagonists of morphine-like drugs as well as to characterize receptors or binding sites that combine with such agents.
Opioids are generally employed as analgesics, but they may have many other pharmacological effects as well. Morphine and related opioids produce their major effects on the central nervous and digestive systems. The effects are diverse, including analgesia, drowsiness, mood changes, respiratory depression, dizziness, mental clouding, dysphoria, pruritus, increased pressure in the biliary tract, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous systems.
A significant feature of the analgesia produced by opioids is that it occurs without loss of consciousness. When therapeutic doses of morphine are given to patients with pain, they report that the pain is less intense, less discomforting, or entirely gone. In addition to experiencing relief of distress, some patients experience euphoria. However, when morphine in a selected pain-relieving dose is given to a pain-free individual, the experience is not always pleasant; nausea is common, and vomiting may also occur. Drowsiness, inability to concentrate, difficulty in mentation, apathy, lessened physical activity, reduced visual acuity, and lethargy may ensue.
The development of tolerance and physical dependence with repeated use is a characteristic feature of all opioid drugs, and the possibility of developing psychological dependence on the effect of these drugs is a major limitation for their clinical use. There is evidence that phosphorylation may be associated with tolerance in selected cell populations (Louie, A. et al.
Biochem Biophys Res Comm
(1988) 152:1369-75).
Acute opioid poisoning may result from clinical overdosage, accidental overdosage, or attempted suicide. In a clinical setting, the triad of coma, pinpoint pupils, and depressed respiration suggest opioid poisoning. Mixed poisonings including agents such as barbiturates or alcohol may also contribute to the clinical picture of acute opioid poisoning. In any scenario of opioid poisoning, treatment must be administered promptly.
The opioids interact with what appear to be several closely related receptors. Various inferences have been drawn from data that have attempted to correlate pharmacologic effects with the interactions of opioids with a particular constellation of opioid receptors (Goodman and Gilman's,
THE PHARMACOLOGICAL BASIS OF THERAPEUTICS
, 7th ed, pp. 493-95 (MacMillan 1985)). For example, analgesia has been associated with mu and kappa receptors. Delta receptors are believed to be involved in alterations of affective behavior, based primarily on the localization of these receptors in limbic regions of the brain. Additionally, activation, e.g., ligand binding with stimulation of further receptor-mediated responses, of delta opioid receptors is believed to inhibit the release of other neurotransmitters. The pathways containing relatively high populations of delta opioid receptor are similar to the pathways implicated to be involved in Huntington's disease. Accordingly, it is postulated that Huntington's disease may correlate with some effect on delta opioid receptors.
Two distinct classes of opioid molecules can bind opioid receptors: the opioid peptides (e.g., the enkephalins, dynorphins, and endorphins) and the alkaloid opiates (e.g., morphine, etorphine, diprenorphine and naloxone). Subsequent to the initial demonstration of opiate binding sites (Pert, C. B. and Snyder, S. H.,
Science
(1973) 179:1011-1014), the differential pharmacological and physiological effects of both opioid peptide analogues and alkaloid opiates served to delineate multiple opioid receptors. Accordingly, three anatomically and pharmacologically distinct opioid receptor types have been described: delta, kappa and mu. Furthermore, each type is believed to have sub-types (Wollemann, M.,
J Neurochem
(1990) 54:1095-1101; Lord, J. A., et al.,
Nature
(1977) 267:495-499).
All three of these opioid receptor types appear to share the same functional mechanisms at a cellular level. For example, the opioid receptors cause inhibition of adenylate cyclase, and inhibition of neurotransmitter release via both potassium channel activation and inhibition of Ca
2+
channels (Evans, C. J., In:
Biological Basis of Substance Abuse
, S. G. Korenman & J. D. Barchas, eds., Oxford University Press (in press); North, A. R., et al.,
Proc Natl Acad Sci USA
(1990) 87:7025-29; Gross, R. A., et al.,
Proc Natl Acad Sci USA
(1990) 87:7025-29; Sharma, S. K., et al.,
Proc Natl Acad Sci USA
(1975) 72:3092-96). Although the functional mechanisms are the same, the behavioral manifestations of receptor-selective drugs differ greatly (Gilbert, P. E. & Martin, W. R.,
J Pharmacol Exp Ther
(1976) 198:66-82). Such differences may be attributable in part to the anatomical location of the different receptors.
Delta receptors have a more discrete distribution within the mammalian CNS than either mu or kappa receptors, with high concentrations in the amygdaloid complex, striatum, substantia nigra, olfactory bulb, olfactory tubercles, hippocampal formation, and the cerebral cortex (Mansour, A., et al.,
Trends in Neurosci
(1988) 11:308-14). The rat cerebellum is remarkably devoid of opioid receptors including delta opioid receptors.
Several opioid molecules are known to selectively or preferentially bind delta receptors. Of the vertebrate endogenous opioids, the enkephalins, A particularly met-enkephalin (SEQ ID NO:1) and leu-enkephalin (SEQ ID NO:2), appear to possess the highest affinity for delta receptors, although the enkephalins also have high affinity for mu receptors. Additionally, the deltorphans, peptides isolated from frog skin, comprise a family of opioid peptides that have high affinity and selectivity for delta receptors (Erspamer, V., et al.,
Proc Natl Acad Sci USA
(1989) 86:5188-92).
A number of synthetic enkephalin analogues are also delta receptor-selective including (D-Ser
2
) leucine enkephalin Thr (DSLET) (SEQ ID NO:3) (Garcel, G. et al.
FEBS Lett
(1980) 118:245-247),and (D-Pen
2
, D-Pen
5
) enkephalin (DPDPE) (SEQ ID NO:4) (Akiyama, K. et al.,
Proc Natl Acad Sci USA
(1985) 82:2543-2547).
Recently a number of other selective delta receptor ligands have been synthesized, and their bioactivities and binding characteristics suggest the existence of more than one delta receptor subtype (Takemori, A. E., et al.,
Ann Rev Pharm Toxicol
, (1992) 32:239-69; Negri, L., et al.,
Eur J Pharmacol
(1991) 196:355-335; Sofuoglu, M., et al.,
Pharmacologist
(1990) 32:151).
Although the syntrhetic pentapeptide 2dAla, 5dLeu enkephalin (DADLE) (SEQ ID NO:5) was considered to be delta-selective, it also binds equally well to m

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