Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1996-08-22
1999-09-28
Degen, Nancy
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 914, 4353201, 435325, 536 231, 536 241, C12Q 168, C12P 1934, C12N 1563, C07H 2104
Patent
active
059586834
DESCRIPTION:
BRIEF SUMMARY
The current invention concerns the use of a receptor from the RZR/ROR receptor family or of a functional fragment thereof in a test of a compound for anti-autoimmune, anti-arthritic, anti-tumor, melatonin-like and/or melatonin-antagonistic activity and the production of a receptor ligand complex comprising said receptor or a functional fragment thereof and a ligand of said receptor. Described is also a method for testing compounds for said agonists or antagonists (screening for ligands) and the active compounds identified therewith.
INTRODUCTION
Small lipophilic substances like retinoic acid (RA), 1,25-dihydroxyvitaminD.sub.3 (VD), thyroid hormone (T3) and steroid hormones regulate a number of developmental and physiological processes in vertebrates and in invertebrates by binding to specific receptors that function directly as transcription factors. These ligand-dependent transcription factors are members of the nuclear receptor superfamily.
The nuclear receptor superfamily also includes structurally related proteins for which no ligand has been identified yet and therefore are referred to as orphan receptors (O'Malley et al., Mol. Endocrinol. (1992), 6, 1259-1361). Examples of such orphan receptors are peroxisome-proliferator activated receptors (PPARs) and chicken ovalbumin upstream promoter transcription factor (COUP-TFs). Despite large diversity in function, two conserved zinc-finger motifs which are involved in binding to DNA appear in all members of this superfamily.
Recently, a novel orphan receptor family has been identified via a reverse transcription-polymerase chain reaction (RT-PCR) strategy (Becker-Andre et al., Biochem. Biophys. Res. Com. (1993), 194, 1371-1379; Becker-Andre et al., Keystone Symposium, Feb. 7-13, 1994, Taos, N. Mex., p.376). RZR/RORs are able to bind as monomers to their specific response elements, but they seem to interact with certain constellations of binding sites cooperatively as homodimers. RZR/RORs show constitutive transactivation and despite different approaches no ligands have been isolated so far for the RZR/ROR receptor family and therefore, it has been assumed, that RZR/RORs may provide constitutive rather than ligand-inducible transactivation.
Surprisingly, it has now been found, that melatonin is a natural ligand of the RZR/ROR receptor family. It was only known that melatonin is a ligand of a membrane receptor, which has been recently cloned from frog skin (Ebiswawa et al., Proc. Natl. Acad. Sci. USA (1994), 91, 6133-6137) and from mamalian tissues (Reppert et al., Neuron (1994), 13, 1177-1185). Melatonin is the major hormon of the pineal gland, but it is also produced in extrapinal tissues. It lightens skin color in amphibians by reversing the darkening effect of MSH (melanotropin). Melatonin is a transmitter of photoperiodic information and is a regulator of seasonal reproductive cycles in photoperiodic animals. It has been shown also that melatonin is involved in thermoregulation and neuroimmunoregulation (Fraschini and Reiter, Eds., Plenum Press N.Y., London 1991).
Melatonin has a short half life in animals and man and it is therefore surprising for melatonin to be a ligand of a nuclear receptor.
As a further surprise, synthetic chemical substances have also been identified as artificial ligands of the RZR/ROR receptor family. Said compounds are known and show anti-autoimmune, anti-arthritic and/or anti-tumor activity (EP-A-494047, EP-A-508955, EP-A-548017, EP-A-548018, CH-511877 and BE-753532). These properties can be demonstrated in vivo, for example in the adjuvant arthritis model in rats in accordance with Wiesenberg et al., Clin. Exp. Immunol. (1989), 78, 245 and the DMBA-tumor model in rats (Schmidt-Ruppin etal., Experentia (1973), 29, 823-825).
These compounds and the pharmaceutically acceptable salts thereof are known to have valuable pharmacological properties in the treatment of diseases of the rheumatoid type. Those diseases include, especially, rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, and other seronegative spondyla
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Missbach Martin
Wiesenberg Irmgard
Degen Nancy
Ferraro Gregory D.
Novartis Corporation
Sandals William
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