Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Patent
1997-04-28
1999-10-19
Saunders, David
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
424427, 427 224, 435377, 514279, 514408, 514912, 514954, A61K 3140, A61K 3144, C12N 100
Patent
active
059688246
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of agents which modulate pathways in which products of so-called opioid peptide precursor genes participate in such a way as to induce cell apoptosis, in particular in tumour cells or lens cells, to methods of treatment employing such agents and to pharmaceutical compositions containing them.
The discovery of receptors within the brain which bind the opium derivative morphine (Pert and Snyder, 1973 Science 179, 1011-1014) preceded the isolation of two pentapeptides with potent opiate agonist activity in bioassay systems (Hughes et al., 1975, Nature, 258, 577-580). The pentapeptides, which differ only in their COOH-- terminal amino acid, were named Met- and Leu-enkephalin to reflect their origin from brain. Peptides containing these sequences are termed opiate or opioid peptides. Enkephalins are widely distributed throughout the central nervous system in enkephalinergic neuronal networks, and also exist in the peripheral nervous system, for example in autonomic ganglia. Data, largely circumstantial, suggest wide-ranging involvement of endogenous opioids for example in the modulation of pain perception, in mood and behaviour, learning and memory, diverse neuroendocrine functions, immune regulation, and cardiovascular and respiratory function.
The observation that the opiate alkaloid nalorphine has a dual action in antagonising the analgesic effect of morphine but also acts as an analgesic in its own right, led to the suggestion that there may be several types of receptor which bind opiate compounds (Martin 1967 Pharmacol. Rev. 19, 463-521). Differential responses to a number of opiates in an animal model suggested three types of opiate receptor--mu, kappa, and sigma (Martin et al., 1976 J. Pharmacol. Exp. Ther. 197, 517-532.) Lord and colleagues (1977 Nature 267, 495-499) compared the activity of morphine and enkephalins in bioassay systems; the results indicated the existence of delta receptors, to which enkephalins bound predominantly, and mu receptors, to which morphine bound preferentially. Synthetic analogues subsequently supported the separation of opioid receptors into three main types--delta, kappa and mu--which has remained a pharmacological classification. Genes encoding these three main receptor types have now been cloned. Prototypic analogues which are selective agonists at the three main receptor types include DAMGO (Tyr-DAla-Gly-MePhe-Glyol) (mu); DPDPE (Tyr-DPen-Gly-Gly-Phe-DPen-OH) (delta); and for the kappa, U50,488. However, the selectivity of these compounds is dose dependent and all have the potential to cross-react with other receptor types (Goldstein 1987 Trends Pharm. Sci. 8, 456-459).
Sequencing of the cloned opioid receptor genes has revealed a substantial degree of amino acid homology between different receptor types (Meng et al., 1993 Proc. Natl. Acad. Sci U.S.A. 90, 9954-9958; Thompson et al., 1993 Neuron 11, 903-913; Evans et al, Science 1992 258, 1952-1955; Kieffer et al., Proc. Natl. Acad. Sci. U.S.A. 1992 89, 12048-12052); this explains the tendency of opioid receptor ligands, even those purported to be selective, to bind more than one type. Alignment of the sequences of the main receptor types with less closely related molecules such as the immunoglobulin superfamily member OBCAM (Schofield et al., EMBO J. 1989 8, 489-495) supports the reported opioid binding properties of the purified OBCAM molecule, and indicates the potential for additional opioid receptor ligands to bind this and other related receptor molecules. Furthermore, additional receptor families, in particular the somatostatin receptors, share close homology with the opioid receptors, and on the basis of these structural similarities (which are illustrated hereinafter in FIG. 1) would also be expected to bing opioid receptor ligands.
Opioid receptor subtypes based on differences in the binding profiles of natural and synthetic ligands have also been suggested, including mu1 and mu2 (Pasternak and Wood 1986 Life Sci. 38, 1889-1898) and kappa1 and kappa2 (Zukin et al., 1988
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Bottger Angelika
Dewar Deborah Ann
Prescott Alan
Spruce Barbara Ann
Cserr Luann
Saunders David
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