IDENTIFICATION OF A UNIQUE RECEPTOR SPECIFIC FOR A PARTICULAR RETINOID INDUCING CELLULAR APOPTOSIS

Abstract: A novel receptor which is not of the RAR type that binds AHPN and believed to be involved in apoptosis is provided. This receptor is useful for identifying ligands that induce apoptosis.

Description: IDENTIFICATION OF A UNIQUE RECEPTOR SPECIFIC FOR A PARTICULAR RETINOID INDUCING CELLULAR APOPTOSIS FTKT-D OF THE INVENTION This invention relates to a novel receptor, found in both nuclear and cytoplasmic cell extracts which binds to a retinoid that induces apoptosis. This receptor is believed to be involved in apoptosis. Therefore, it should be useful as a screening agent for identifying other ligands which induce apoptosis. BACKGROUND OF THE INVENTION Retinoids are defined as substances that can elicit specific biological responses by binding to and activating a specific receptor or set of receptors. Retinoids are known to play a fundamental role in normal cell growth and differentiation. (Roberts, A.B. et al, in "The Retinoids," ed. by M.B. Sporn, A.B. Roberts and D. S. Goodman, Vol. 2, pp. 209-256, Academic Press, Oi ndo, Fla., (1984); Sporn, M.B. et al, J. Amer. Acad. Dermatol, 15:756- 764 (1986)). Multiple retinoic acid nuclear receptors (RARα, β and γ) and retinoid X receptors (RXR , β and γ) have been identified (Evans, R.M., Science, 240:889-895 (1988); O'Malley, B.W., Mol. Endocrin., 4:363-364 (1990); Gudas, L.J. Cell Growth Differ, 3:655-662 (1992)); Lohnes et al, Cell Set, 16 (Suppl): 69-76 (1992). Moreover, numerous isoforms of the various nuclear receptors exist as a result of alternative splicing (Gudas L.J., J. Biol. Chem., 269: 15399-15402 (1994)). Retinoic acid receptors mediate gene transcription through a variety of mechanisms. These nuclear receptors can bind to specific DNA consensus sequences termed retinoid receptor response elements (RAREs or RXREs) which are located in the regulatory regions of the retinoid target genes (Gudas, L.J., Cell Growth Differ., 3:655-662 (1992); Lohnes et al, Cell Scl, 16 (Suppl.):69-76 (1992)). Nuclear receptor binding to these response elements preferably occurs through heterodimer formation between the RAR and RXR, although homodimer binding and subsequent gene activation has also been found (Hermann et al, Mol. Endocrinol, 6:1153-1162 (1992); Leid et al, Cell, 68:377-395 (1992); Zhang X, Nature, 355:441-446 (1992)). The RXRs can mediate gene transcription via heterodimer formation with the RARs, with the vitamin D, thyroid hormone (Yu et al, Cell, 67:1251-1266 (1991); Hermann et al, Mol. Endocrinol, 6:1153-1162 (1992); Kliewer et al, Nature, 355:446-449 (1992); Leid et al, Cell, 68:377-395 (1992); Zhang et al, Nature, 355:441-446 (1992)), and a number of orphan receptors. (Apfel et al, Mol. Cell BioL, 14:7025-7035 (1994); Song et al, Proc. Natl. Acad. Scl, USA 91 : 10809-10813 (1994)). These orphan receptors can, in turn, inhibit the activity of RARs and thyroid nuclear receptors (TRs) (Kliewer et al, Proc. Natl. Acad. Scl, USA, 89:1448-1452 (1992); Tran et al, Mol. Cell BioL, 12:4666-4676 (1992); Apfel et al, Mol. Cell BioL, 14:7025-7035 (1994), Casanova et al, Mol. Cell Biol, 14:5756-5765 (1991); Song et al, Proc. Natl. Acad. Scl, USA, 91:10809-10813 (1994)). The retinoid receptor response elements usually consist of direct repeats (DRs) in which the half-sites are separated by a number of base pair spacers. Selectivity for binding appears to be determined by the number of base pairs utilized as spacers, as well as by the sequence of the response element itself (Kim et al, Mol. Endocrinol, 6:1489-1501 (1992); Mader et al, J. Biol. Chem., 268:591-600 (1993)). RAR and RXR inhibition of AP-1 -mediated gene transcription that does not require RAR or RXR binding to DNA has also been observed (Pfahl, Endocrin. Reviews, 14:651-658 (1993), and references cited therein); RAR and RXR when complexed to their ligands have been shown to inhibit c- Jun/c-Fos binding to the AP-1 consensus sequence and subsequent gene activation (Pfahl, Endocrine Reviews, 14:651-658 (1993), and references cited therein). Negative regulation of transcription by RA can apparently also occur by means that do not involve RAR binding to the promoter region but by inhibiting enhancer activity (Gudas, J. Biol. Chem., 269: 15399-15402 (1994)). In addition, negative regulation of RAR-mediated, as well as TR- mediated, gene transcription occurs by the competitive binding of the orphan receptor coup and v-ErbA to RARE and TREs (Tran et al, Mol. Cell. Biol, 12:4666-4676 (1992); Hermann et al, Oncogene, 8:55-65 (1993)). Most cell types express more than one RAR and RXR receptor. RAR homologous recombination studies have suggested that RAR functional redundancy exists among the different RARs (Li et al, Proc. Natl. Acad. Scl, USA, 90:1590-1594 (1993); Lohnes et al, Cell, 73: 643-658 (1993); Lufkin et al, Proc. Natl. Acad. Scl, USA, 90:7225-7229 (1993)). However, other studies have indicated that the various receptor subtypes possess distinct functions and may indeed modulate the activity of distinct genes (Nagpal et al, Cell, 70:1007-1019 (1992); Boylan et al, Mol. Cell BioL, 15:843-851 (1995)). Evidence also suggests a unique role for each of the receptor subtypes: (1) receptor selectivity towards specific trans activating response elements has been demonstrated (Nagpal et al, Cell, 70:1007-1019 (1992)); and (2) specific cell types have become refractory to the antiproliferative and differentiating effects of RA with the loss of one receptor subtype, despite the presence of other RAR subtypes (Sheikh et al, J. Cell Biochem., 53:393-403 (1993); Moasser et al, Oncogene, 9:833-840 (1994)). The RARs bind both RA and its isomer 9-cis-RA, while the RXRs only bind 9-cis-RA (Allenby et al, J. Biol. Chem., 269: 16689-16695 (1995), and references cited therein). To further document a unique function for each receptor subtype, conformationally restricted retinoids have been synthesized that selectively bind to and enhance transcriptional activation by selective RAR and RXR subtypes (Graupner et al, Biochem. Biophys. Res. Commun., 179: 1554-1561 (1991); Lehmann et al, Cancer Res., 61 :4804-4809 (1991), Lehmann et al, Science, 258: 1944-1946 (1992); Dawson et al, in "Retinoids: New Treatments in Research and Clinical Applications", Livrea MA and Packer L., (eds) Marcel Dekker: NY pp 205-221 (1992); Davies et al, Amer. Ass'n of Cancer Res. Conf, Banff, Alberta, Canada, March 15-20 (1993) Abst. B-28; Jong et al, J. Med. Chem., 36:2605-2613 (1993); Reichert et al, from "Mol. Biol. to Therapeutics: Pharmacology of the Skin", Vol. 5, Bernard BA and Shroot B (eds), Karger: B.2d pp 117-127 (1993); Beard et al, Bioorg. Med. Chemical, 4:1447-1452 (1994); and Boehm et al, J. Med. Chem., 37:2936-2941 (1994)). These synthetic receptor-selective retinoids have further confirmed the uniqueness of specific RAR subtypes in modulating RA responses in various cell types (Rudd et al, Cancer Letter, 73:41-49 (1993); Sheikh et al, J. Biol. Chem., 269:21440-21447 (1994)). Recently, a series of synthetic retinoids has been described that selectively transactivate RARγ (Bernard et al, Bio- chem. Biophys. Res. Comm., 186(2):977-983 (1992)). Because of the ability of retinoids to affect cell growth and differentiation, these compounds have been disclosed to be useful for the treatment or prevention of diseases and conditions involving abnormal cell proliferation and differentiation. For example, the usage of retinoids as efficient therapeu- tics for the treatment of various skin diseases and neoplasms has been reported (Roberts, A. B. and Sporn, M.B., in "The Retinoids", Sporn et al, pp 209-286, Academic Press, Orlando, Fla; Bollag et al, Ann. Oncol, 3:513-526 (1992); Smith et al, J. Clin. Oncol, 10:839-864 (1992)). To date, the best results of retinoid therapy have typically been achiev- ed with a regimen which combines retinoid administration with the administration of other differentiation or cytotoxic agents. Besides retinol and retinoic acid, isotretoin (13-cis-retinoic acid) and etretinate have been used, as well as 9-cis retinoic acid and N-(9-hydroxyphenyl)retinoid. The most convincing results have been documented in the field of dermatological disorders, where topical application can circumvent the toxic effects sometimes observed during systemic administration of retinoids. For example, retinoids have been reported to be useful for the treatment of a variety of dermatoses including psoriasis, cystic acne, cutaneous disorders of keratinazation, among others. Besides dermatological disorders, retinoids have important potential as anti-cancer agents. For example, retinoid compounds have been disclosed to have potential for the prevention of skin cancer, for the treatment of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) for the treatment of other hematopoietic malignancies such as myelodysplastic syndrome, juvenile chronic myelogenous leukemia, Sezary syndrome, squa- mous cell carcinomas of the upper aerodigestive tract, non-small lung cancer, and human head and neck carcinomas. (See Pfahl et al, Vitamins and Hormones, 49:327-382 (1993) at 363-366, which reviews the usage of retinoids as therapeutics). The Applicant recently discovered that a specific adamantyl retinoid derivative 6-(3-(l-adamantyl)-4-hydroxyphenyl)-2-naphthoic acid (AHPN) induces apoptosis of a variety of different cells, some of which are resistant to the proliferation and differentiating effects of retinoids. Also, other adamantyl retinoids have been found to exhibit similar apoptosis inducing activity. However, while some retinoids have been reported to have potential as anticancer agents, and specifically for inducing apoptosis, the identification of retinoids having improved therapeutic properties which are suitable for the treatment or prevention of cancer would be highly beneficial. In particular, the identification of retinoids which induce apoptosis would be highly beneficial. Moreover, the identification of receptor(s) involved in the induction of apoptosis, e.g., the receptor bound by AHPN, would be highly useful as a screening agent for selecting other apoptosis inducing compounds. OBJECTS OF THE INVENTION It is an object of the invention to provide novel methods and materials for identifying ligands that induce apoptosis. More specifically, it is an object of the invention to identify a novel receptor that is believed to be involved in apoptosis, i.e., "programmed cell death". It is another object of the invention to use such novel receptor as a screening agent, e.g., in competition binding assays, to select other receptors that induce apoptosis. It is another object of the invention to provide a nucleic acid sequence encoding such novel receptor. It is still another object of the invention to provide cells which express a nucleic acid sequence encoding a novel receptor that induces apoptosis and to use such cells in screening assays for selecting other ligands that induce apoptosis. It is another object of the invention to use the nucleic acid sequence encoding such novel receptor, or fragments thereof, as a probe to identify DNAs encoding related receptors. It is a specific object of the invention to use AHPN and radioisotopi- cally labeled derivatives thereof in competitive binding assays to identify other ligands that induce apoptosis. It is another specific object of the invention to use such radioisotopi- cally labeled derivatives of AHPN to qualitatively and/or quantitatively assess the expression of receptor(s) involved in apoptosis by selected cell types. It is another object of the invention to provide a novel means of synthesizing radioisotopically labeled forms of AHPN and novel intermediates and products produced by such synthesis procedure. It is yet another object of the invention to use such radioisotopically labeled AHPN derivatives in metabolism assays. BRIEF DESCRIPTION OF THE INVENTION As discussed in detail below, the present invention is directed to a novel receptor, which is not of the RAR or RXR type that is believed to be involved in apoptosis that binds to AHPN. This receptor is apparently expressed in both the nuclear and cytoplasmic fractions of cells. This receptor has an apparent molecular weight of about 90 kDa. Binding studies, and this apparent molecular weight, the results of which are discussed in detail infra, strongly suggest that this receptor is not of the RAR or RXR type, and is of a highly unique nature. This receptor specifically binds to AHPN, an adaman- tyl retinoid compound shown to induce apoptosis in a variety of cell types, many of which are resistant to the proliferative and/or differentiating effects of retinoids. The binding of AHPN to this receptor is only minimally displaced by all-trans retinoic acid in a competitive binding assay. In the present invention, a receptor that specifically binds AHPN is intended to refer to a receptor that binds AHPN, wherein the binding of AHPN to such receptor is substantially unaffected by compounds that do not specifically bind to such receptor. "Substantially unaffected" preferably means that at least 75% of the bound AHPN compound remains bound in the presence of an excess of a compound that does not specifically bind such receptor, more preferably at least 90% remains bound and most preferably in excess of 95% remains bound. In the present invention, a compound which only "minimally displaces" the binding of a compound to a receptor, e.g., the minimal displacement of AHPN to its receptor by the addition of an excess of all-trans retinoic acid means that at most about 25% of bound compound, e.g., AHPN is displaced, more preferably at most about 10% is displaced and most preferably 5% or less of the bound compound, e.g., AHPN, is displaced from its receptor in a competitive binding assay. The AHPN compound also binds to the RARγ receptor. Consequent- ly, this receptor should be well suited as a screening agent to select other ligands that induce apoptosis. Also, the corresponding DNA may be used to identify related receptors. These receptors will also provide useful screening agents for selecting ligands that induce apoptosis. Also, the present invention is directed to the use of AHPN and radioisotopically labeled forms thereof as a screening agent to assess qualita- tively and/or quantitatively the expression of the subject novel receptor by selected cells, e.g., tumor cell lines or other cells for which the modulation of apoptosis is therapeutically desirable. Such screening agents will be useful in both in vitro and in vivo assays for selecting target cells susceptible to apoptosis. Also, the present invention is directed to a novel means of synthesizing radioisotopically labeled derivatives of AHPN as well as the novel intermediates and radioisotopically labeled derivatives produced by such methods. This method will, in general, comprise the following steps: (i) preparation of a halogenated (preferably bromine) alkyl ester of AHPN, preferably a methyl ester; (ii) hydrolysis of the halogenated alkyl ester; (iii) reduction using a radioisotope containing reducing agent, preferably a deuterium or tritium containing reducing agent; and (iv) cleavage of the methoxy group contained therein, e.g., by the use of sodium alkylthiolate, wherein the reduction and cleavage steps may be effected in either order. Also, the present invention embraces to carbon 13 or carbon 14 containing AHPN derivatives, and the use thereof as screening agents to identify other ligands that induce apoptosis. These derivatives can be pro- duced by replacing the benzene ring or the carboxylic acid substituent of AHPN with a C 13 or C 14 labeled carbon dioxide or benzene. As discussed in further detail infra, these radioisotopically labeled forms are also useful in metabolism studies in in vitro and in vivo systems. BRIEF DESCRIPTION OF THE FIGURES LEGENDS Fig. 1 Scatchard analysis of [ 3 H] 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid binding to MDA-MB-468 nuclear extracts. K D value is the mean of three separate experiments. Binding was performed as described in methodology section infra. Fig. 2 Competitive binding between tRA (20 μM) or 6-[3-(l-adamantyl)-4- methoxy phenyl]-2-naphthalenecarboxylic acid (20 μM) for the [ 3 H] 6- [3-(l-adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid receptor in nuclear extracts of HL-60R. Fig. 3 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid inhibition of [ 3 H] tRA binding to MDA-MB-468 nuclear- extracts. Unlabeled 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid and tRA were added to final concentrations of 20 μM and 1 μM respectively, while [ 3 H] tRA was added to a final concentration of lOnM. Fig. 4 Process for preparing [ 3 H] 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid (compound VI) via the illustrated reaction schemes. DETAILED DESCRIPTION OF THE INVENTION Retinoids exert their antiproliferative and differentiating effects by binding to specific nuclear receptors termed RARs and RXRs. (Giguere, V., Endocrine Reviews 15, 51-79 (1994)). These nuclear receptors in turn bind to specific consensus sequences (RAREs, RXREs) located in the regulatory regions of genes modulating their expression. (Giguere, V., Endocrine Reviews 15, 51-79 (1994)). Previously, the Applicant identified a retinoid compound 6-[3-( 1 - adamantyl)-4-methoxy phenyl] -2-naphthalenecarboxylic acid (AHPN) which induces apoptosis in a variety of cell types, many of which display resistance to the antiproliferative and/or differentiating effects of retinoids. (Shao, Z-M., Dawson, M.I.. Li, X.-S., Rishi, A.K., Sheikh, M.S., Han, Q.-X., Ordonex, J.V., Shroot, B., and Fontana, J.A. Oncogene, 11, 493-504 (1995); Bernard, B.A., Bernardon, J.-M., Delescluse, C, Martin, B., Lenoir, M.-C., Maignan, J., Charpentier, B-, Pilgrim, W.R., Reichert, U., and Shroot, B., Biochem. Biophys. Res. Commun., 186, 977-983 (1992); Li, X-S., Rishi, A.K., Shao, Z.-M., Dawson, M.I. Jong, L., Shroot, B., Reichert, U., Ordonez, J. and Fontana, J.A. Cancer Res., 56, 5055-5062, (1996)). The present invention relates to the discovery that this retinoid binds to a unique receptor which has been found in both the nuclear and cytoplasmic fractions of cells. The 6-[3- (l-adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid (AHPN) receptor differs from the RARs and RXRs in its ligand specificity. Binding of AHPN to its receptor, while minimally displaced by all trans retinoic acid (tRA), which actively binds to the RARs, is displaced by AHPN. In addition, AHPN does not compete with [ 3 H] tRA binding. The AHPN compound was initially synthesized as a conformationally restricted retinoid which displayed selective binding to the RARγ receptor. (Bernard, B.A., Bernardon, J.-M., Delescluse, C, Martin, B., Lenoir, M.-C, Maignan, J., Charpentier, B-, Pilgrim, W.R., Reichert, U., and Shroot, B., Biochem. Biophys. Res. Commun., 186, 977-983 (1992). AHPN was observed to display a 3-fold higher kD for the receptor RARγ than all trans retinoic acid (tRA) and further displayed a 9-fold and 70-fold higher kD than tRA for the RARβ and RARα receptors respectively. (Bernard, B.A., Bernardon, J.- M., Delescluse, C., Martin, B., Lenoir, M.-C, Maignan, J., Charpentier, B-, Pilgrim, W.R., Reichert, U., and Shroot, B., Biochem. Biophys. Res. Commun., 186, 977-983 (1992). Also, AHPN was found to be a potent inducer of G, cell cycle arrest and apoptosis in breast carcinoma cells both resistant and sensitive to the antiproliferative action of tRA, (Shao, Z-M., Dawson, M.I.. Li, X.-S., Rishi, A.K., Sheikh, M.S., Han, Q.-X., Ordonex, J.V., Shroot, B., and Fontana, J.A. Oncogene, 11, 493-504 (1995)). That AHPN exerted its action through a RAR/RXR independent mechanism was suggested by a number of observations: (i) retinoids, which displayed higher selectivity and a lower kD than 6- [3-( 1 -adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid for RARγ were inactive against the tRA resistant 6-[3-(l-adamantyl)-4-methoxy phenyl] -2-naphthalenecarboxylic acid sensitive cells (data not shown); (ii) 6-[3-( 1 -adamantyl)-4-methoxy phenyl] -2-naphthalenecarboxylic acid is significantly less potent than tRA in its ability to transactivate endoge- nous retinoid receptors on transfected β2 RARE and (TRE) 3 _-TK reporter constructs in breast carcinoma cells both sensitive and resistant to the antiproliferative effects of tRA but in which 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid induces apoptosis (Shao, Z-M., Dawson, M.I.. Li, X.-S., Rishi, A.K., Sheikh, M.S., Han, Q.-X., Ordonex, J.V., Shroot, B., and Fontana, J.A. Oncogene, 11, 493-504 (1995)); (iii) HL-60R cells, which do not possess the RARβ and RARγ nuclear receptors and a truncated RARα receptor, are resistant to the antiproliferative and differentiating effects of tRA. (Li, X-S., Rishi, A.K., Shao, Z.-M., Dawson, M.I. Jong, L., Shroot, B., Reichert, U., Ordonez, J. and Fontana, J.A. Cancer Res., 56, 5055-5062, (1996); Robertson, K.A., Emani, B., and Collins, S.J. Blood, 80, 1885-1889 (1992); Robertson, K.A., Emani, B., Mueller, L., and Collins, S.J. Mol. Cell. Biol., 12, 3743-3749, (1992); Nagy, L. Thomazy, VA., Shipley, G.L., Fesus, L., Lamph, W., Heyman, R.A., Chandraratna, R.A.S. and Davies, P.J.A. Mol. Cell. Biol. 15, 3540-3551 (1995)). Notwithstanding this fact, AHPN induces apoptosis in this cell line with an ED 50 25nM. These results strongly suggested that AHPN induces apoptosis in cells through a RAR/RXR independent pathway. These results were further supported by Scatchard analysis. Specifically, when Scatchard analysis of [ 3 H]-6-[3-( 1 -adamantyl)-4-methoxy phenyl] -2-naphthalenecarboxylic acid binding to nuclear extracts of MDA-MB-468 human breast carcinoma cells in the presence of 20μM tRA (to block RARα. and RARγ binding) was performed, a kD of 10 nM and a β max of 0.1615nM (215 fmole/mg protein) was obtained (Fig. 1). Non specific binding represented approximately 25 percent of the total counts bound. To further assess the specificity of this binding, the ability of a 800- fold excess of tRA or AHPN to inhibit [ 3 H]-6-[3-(l-adamantyl)-4-methoxy phenyl] -2-naphthalenecarboxy lie acid binding was examined. As shown in Fig. 2, the addition of tRA had no effect on AHPN binding while the addition of excess unlabeled 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid reduced the binding by greater than 80 percent. MDA-MB-468 human breast carcinoma cells, like the majority of estrogen receptor negative breast carcinoma cells, are refractory to the antiproliferative effects of tRA; do not possess RARβ; express low levels of RARα; and only express moderate levels of RARγ. Also, they are exquisitely sensitive to AHPN-mediated apoptosis. (Sheikh, M.S., Shao, Z.-M, Li, X.-S., Dawson, M.I. Jetten, A.M., Wu, S., Conley, B.A., Garcia, M. and Fontana, J.A. J. Biol. Chem., 269, 21440-21447 (1994); van den Burg, B., van der Leede, B-.J., M-, Kwakkenbos-Isbrukner, L., Salverda, S., de Laat, S.W. and van den Saag, P.T. Mol. Cell. Endocrinology, 19, 149-157 (1993); Swissheim, K., Ryan, K., Lee, X., Tsou, H.C., Peacocke, M., and Sager, R. Cell Growth and Diff, 5, 133-141 (1994)). The inventors thereupon examined [ 3 H]-6-[3-(l- adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid binding to RARα as well as RXRα and RXRβ in vitro utilizing recombinant receptors. No binding of [ 3 H]-6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid to the RXRs was detected while RARα displayed a kD of 440nM (results not shown). It was also investigated whether 6-[3-(l-adamantyl)-4-methoxy phenyl] -2-naphthalenecarboxylic acid inhibited [ 3 H]-tRA binding to nuclear extracts obtained from HL-60R cells as well as MDA-MB-468 cells. As shown in Fig. 3, AHPN did not compete with [ 3 H]-tRA binding in nuclear extracts obtained from MDA-MB-468 cells. No specific binding of either [ 3 H]-tRA or [ 3 H]-TTAB (arotinoid acid) to a nuclear extract obtained from HL-60R cells was detected (data not shown). These in vitro binding data strongly support a conclusion that AHPN is not binding to RARs or RXRs, but rather to a unique receptor. A similar [ 3 H]-6-[3-(l-adamantyl)-4-methoxy phenyl] -2-naphthalene- carboxylic acid binding protein was also found in cytosolic extracts obtained from HL-60R cells (data not presented herein). The RARs and RXRs possess molecular weights of 50kDa and 54kDa respectively. (Petkovich, M., Brand, N.J., Krust, A. and Chambon, P. Nature, 330, 444-450 (1987); Mangelsdorf, D.J., Ong. E.S., Dyck, J.A. and Evans, R.M. Nature, 345, 224-229 (1990)). We further characterized the AHPN receptor as to its mass. [ 3 H]-6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid saturable binding was confined to a single symmetrical peak corresponding to an apparent molecular weight of 90 kDa. These disparate molecular weights further supports the inventors' conclusion that this receptor is not an RAR or RXR type receptor. As discussed, AHPN triggers apoptosis in a number of cell lines. (Shao, Z-M., Dawson, M.I.. Li, X.-S., Rishi, A.K., Sheikh, M.S., Han, Q.-X., Ordonex, J.V., Shroot, B., and Fontana, J.A. Oncogene, 11 , 493-504 (1995); Li, X-S., Rishi, A.K., Shao, Z.-M., Dawson, M.I. Jong, L., Shroot, B., Reichert, U., Ordonez, J. and Fontana, J.A. Cancer Res., 56, 5055-5062, (1996)). The mechanism(s) involved by which 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid triggers apoptosis as well as the upregulation of a number of genes p21 WAF1Y IP1 including p21 AF1 IP1 is unclear. (Shao, Z-M., Dawson, M.I.. Li, X.-S., Rishi, A.K., Sheikh, M.S., Han, Q.-X., Ordonex, J.V., Shroot, B., and Fontana, J.A. Oncogene, 11, 493- 504 (1995); Li, X-S., Rishi, A.K., Shao, Z.-M., Dawson, M.I. Jong, L., Shroot, B., Reichert, U., Ordonez, J. and Fontana, J.A. Cancer Res., 56, 5055- 5062, (1996)). Upregulation of p21 WAF1/CIP1 mRNA expression occurs within 30 min, suggesting a rapid signal transduction mechanism. (Li, X-S., Rishi, A.K., Shao, Z.-M., Dawson, M.I. Jong, L., Shroot, B., Reichert, U., Ordonez, J. and Fontana, J.A. Cancer Res., 56, 5055-5062, (1996)). The results of the present invention strongly suggest that AHPN induces apoptosis by binding to a unique protein receptor which has been found in both the nuclear and cytoplasmic fractions of cells. Therefore, AHPN and isotopically labeled forms thereof should provide useful screening agents for identifying other receptors involved in apoptosis. Further, these compounds should be useful for the affinity purification of such receptors and for assaying the expression of such receptors by selected cell types (both quantitatively and qualitatively). As discussed in further detail infra, isotopically-labeled AHPN derivatives will include, in particular, AHPN substituted with radiolabels including deuterium, tritium, carbon 13 or carbon 14, iodine 125, indium 131 , yttrium 90, and other well known radiolabels used for diagnostic and/or therapeutic purposes. Preferably the radiolabel will comprise deuterium or tritium, and most preferably tritium. The AHPN can be mono-, di- or poly-isotopically-labeled. Preferably, it is di-isotopically-labeled. The 6 (3-(l-Adamantyl)-4-hydroxyphenyl)-2-naphthoic acid com- pound of the present invention has the following formula: This compound is also referred to as "CD437" by the present inventors. Accordingly, in the present disclosure, AHPN, CD437 and 6 (3-(l- adamantyl)-4-hydroxyphenyl)-2-naphthoic acid refer to the same compound. The isotopically-labeled 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid used for screening will preferably comprise [ 3 H]- 6-[3-(l-adamantyl)-4-hydroxy-5-[ 3 H]-phenyl]-2-naphthalenecarboxylic acid having the following formula: This isotopically-labeled AHPN derivative is referred to interchangeably in this application as [ 3 H] CD437 or [ 3 H]AHPN, or [Η]-6-[3-(l-adamantyl)-4- hydroxy-5-[ 3 H]-phenyl]-2-naphthalenecarboxylic acid. The radioisotopically labeled AHPN or CD437 derivatives defined above preferably will have a specific activity which is greater than 20Ci/mmole and more preferably at least equal to 50 Ci/mmole or approximately 1850 GBq/mmole. As discussed above, the present invention also provides a novel method for the preparation of the above-identified isotopically-labeled compounds. This synthesis is depicted schematically in Figure 4. This method is principally characterized by the fact that a mono-, di- or poly- halogenated alkyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid is prepared (compound II). (Figure 4) Depend- ing on the number of equivalents of the halogenating agent selected, up to five atoms can be added. The halogenated alkyl ester is then hydrolyzed, for instance in a methanol medium in the presence of sodium hydroxide solution. The resultant compound III (Figure 4) is reduced using a deuterium or tritium containing reducing agent to provide compound IV. (Figure 4) The phenol VI (Figure 4) is obtained by cleavage of the methoxy group, e.g., using sodium alkylthiolate. Alternatively, the methoxy radical can be cleaved before reduction. The alkyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid used in such reaction will preferably comprise the methyl ester. This compound may be prepared by known methods, preferably as described in Example 9 of US 4,717,720. The halogenated derivative used as the starting material will preferably comprise a brominated derivative. However, other halogen derivatives should be suitable also. The present invention also relates to the intermediate compounds of the process as described above. The reduction of the halogenated derivative is preferably carried out at room temperature and under ambient pressure, for example, at 15-30°C under a pressure of 1 bar. However, these methods can be varied using known procedures. As discussed, the present invention also embraces the production of C 13 or C 14 isotopically labeled derivatives of AHPN. Isotopically-labeled AHPN substituted with carbon 13 or carbon 14 can be obtained by replacing the benzene ring or the carboxylic acid. The replacement of such functional groups, through the use of reagents such as isotopically-labeled carbon dioxide or benzene, can be effected by well known methods. As noted, the isotopically labeled compounds are useful screening agents. For example, they may be used to assess qualitatively and/or quantitatively the expression of the subject novel receptor (or related receptors) and/or RARγ on specific types of cells. Also, these labeled compounds may be used to identify related receptors. This is highly useful as such receptors potentially also will be involved in apoptosis. Also, these screening agents may be used in affinity assays for the affinitiy purification of the subject receptor, and in competitive binding assays to identify other ligands that induce apoptosis. For example, the isotopically-labeled 6-[3-( 1 -adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid can be used in a competition binding assay against a ligand potentially to be tested for apoptosis activity. By comparing the degree to which the isotopically-labeled 6-[3-(l-adamantyl)-4- methoxy phenyl]-2-naphthalenecarboxylic acid and ligand bind to the subject receptor and/or RARγ, relative to the degree of binding of the isotopically- labeled 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid to the subject receptor and/or RARγ in the absence of the ligand, the activity of the ligand on the new receptor and/or RARγ can be determined. This should correlate to the ability of such ligand to induce apoptosis. Methods for conducting such competition binding assays are well known to those skilled in the art. For example, one method of conducting such an assay comprises initially incubating the isotopically-labeled AHPN in a medium containing the subject receptor and/or RARγ until the isotopically- labeled AHPN becomes bound to the subject receptor and/or RARγ to the point of saturation. Thereafter, the bound receptor of the present invention and/or RARγ is washed and incubated with an excess (e.g., 200 times) of the ligand to be tested. By comparing the quantity of bound isotopically-labeled AHPN displaced by the ligand to be tested, the relative selective activity of the ligand on the subject receptor and/or RARγ, if any, can be determined. Alternatively, when the saturation curve of the isotopically-labeled 6- [3-( 1 -adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid to the subject receptor and/or RARγ has been previously determined, then the isotopically-labeled 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthalenecarboxylic acid and ligand can be incubated with the subject receptor and/or RARγ at the same time, and the degree of exclusion of the binding of the isotopically-labeled AHPN to the subject receptor and/or RARγ used to measure the relative selective activity of the ligand on the new receptor and/or RARγ, if any. The subject receptor and/or RARγ proteins used in the competition binding assays of the methods of the present invention will generally be recovered from cell lysates of an appropriate cell or cell culture, e.g., one which has been transfected with a recombinant plasmid capable of expressing the subject novel receptor and/or RARγ proteins. However, any appropriate means of producing a sufficient quantity of the subject receptor and/or RARγ receptor to allow for the conducting of the identification methods of the present invention can be employed. Any biologically compatible medium in which the competition binding assays of the present invention can function is considered to be within the scope of the present invention. To help ensure an accurate measurement of the amount of isotopically- labeled AHPN compound that can bind to the subject receptor and/or RARγ, it is preferred that the specific binding of the isotopically-labeled AHPN derivative be determined by titrating the bound isotopically labeled AHPN against an excess quantity of the same compound in a non-labeled form. For example, the isotopically-labeled AHPN is first incubated with the subject receptor and/or RARγ to the point of saturated binding. An appropriate binding curve is then generated which shows total binding, both specific binding to the subject receptor and/or RARγ pocket, and nonspecific binding to other associated structures (e.g. lipids). Thereafter, the subject receptor and/or RARγ bound with the isotopically-labeled AHPN is incubated with a large excess of the non-labeled version of the isotopically-labeled AHPN (e.g., 200 times or greater concentration). Any isotopically-labeled AHPN that remains bound, as shown by an appropriate binding curve, represents nonspecifically bound isotopically-labeled AHPN. By subtracting the nonspecifically bound protein from the total bound protein, a binding curve can be generated which shows the total specific binding of the isotopically- labeled AHPN to the subject novel receptor and/or RARγ. This in turn provides a reference point for determining the concentration of a tested ligand that displaces the isotopically-labeled compound from the new receptor and/or RARγ. Thereby, other ligands that preferably induce apoptosis comparably or even better than AHPN may be selected. Another use of the isotopically-labeled AHPN derivatives provided herein are in metabolism studies. This may be effected using a mass spectrometer to locate metabolites of both the isotopically-labeled and non-labeled ligands. For example, a 1:1 mixture of a 13 CD 3 isotopically-labeled AHPN and a non-labeled AHPN are administered to an in vitro system (e.g., an appropriate cell line) or an in vivo system (e.g., an animal model, such as laboratory mice), followed by extraction of metabolites from the system (e.g., whole cell lysates or animal bodily fluids). The metabolites can then be identified using known methods. As discussed, the novel receptor which is disclosed herein, based on the fact it binds AHPN, a compound known to induce apoptosis, is believed to be involved in cell apoptosis. Therefore, this receptor should be useful for the identification of other ligands that induce apoptosis. As explained above, the identification of other ligands that induce apoptosis may be identified in competition binding assays such as are known in the art and described above. In general, these assays will evaluate whether a particular ligand significantly competes with AHPN or an isotopic labeled form thereof in binding the novel receptor disclosed herein. In order to effect such assays, a source of the subject receptor of sufficient purity and quantity to conduct the assay is required. The purification of a suitable receptor containing extract is disclosed in the example which follows. It is expected that other mammalian cells, e.g., others for which AHPN induces apoptosis, will also express this receptor. Cells which express this receptor or similar receptors can be identified using radioisotopically labeled derivatives of AHPN as a radiomarker. These cells can then be utilized as an alternative source of receptor. Still alternatively, the subject receptor may be sequenced by known methods, and the sequence utilized to construct hybridization probe(s) in order to isolate the compounding nucleic acid sequence from a DNA library. Methods of purifying and sequencing receptors and constructing probes based on such sequences are well within the level of ordinary skill in the art. As discussed above, the subject receptor is believed to be unique relative to other known nuclear receptors, e.g., it is distinct from RAR and RXR receptors. The uniqueness is supported by the molecular weight and binding studies discussed herein. Given the unique properties of the subject receptor, the DNA encoding such receptor should be useful as a hybridization probe, i.e, to identify DNAs encoding related receptors, which also may be involved in apoptosis. These hybridization assays will be conducted by known methods. Such DNAs will exhibit a high level of sequence identity with the subject DNA, i.e., at least 50% of the residues will likely be conserved and preferably 80 - 90% of the residues, or more. Preferably, DNAs which hybridize under conditions of high stringency to a DNA encoding the subject receptor or a fragment thereof will be selected. These DNAs will be sequenc- ed using known methods and expressed by recombinant methods. The resultant expression products will also be useful in assays for selecting other ligands which induce apoptosis. The compounds screened for apoptosis inducing activity with the subject receptor can be selected randomly, e.g., using random compound libraries. Preferably, the compounds screened for apoptosis activity will include retinoid compounds as numerous retinoid compounds have been synthesized and have been reported in the literature. One particular class of retinoid compounds that desirably will be screened for putative apoptosis activity comprises adamantyl containing retinoid compounds. The present Applicant has developed numerous novel adamantyl retinoid derivatives, some of which have already been shown to induce apoptosis. The selection of other putative retinoids having similar apoptosis inducing activity will be determined based on their binding to the novel receptor provided herein. As discussed, a preferred means of identifying such ligands will comprise a competitive binding assay using the radioisotopically labeled forms of AHPN provided herein. Also, once other ligands are identified, these ligands or radiolabeled forms thereof may also be used in competitive binding assays to identify other apoptosis inducing ligands. Ligands that bind the subject receptor potentially should induce apoptosis. Therefore, they are potentially useful as therapeutics in methods wherein induction of apoptosis is therapeutically desirable. For example, these ligands may be used to selectively kill desired target cells, e.g., cancer cells. A particular advantage is that these ligands can be used to selectively kill cells which are resistant to the antiproliferative and/or differentiating effects of other retinoids. Such ligands will be administered by known methods, e.g., orally, topically, intravenously, intramuscularly, rectally, intranasally, transdermally, etc. These ligands will be provided in a pharmaceutically acceptable form, e.g., by the addition of pharmaceutically acceptable excipients and carriers. The entire disclosures of the publications and references referred to above and hereinafter in this specification are incorporated herein by reference. EXAMPLE MATERIALS AND METHODS Binding Assay: [ 3 H]-6-[3-(l-adamantyl)-4-methoxy phenyl] -2-naphthalenecarboxylic acid binding was assessed utilizing a variation of the method described by Allenby et al. (Allenby, G., Janocha, R., Kazmer, S., Speck, J., Grippo, J.F., and Levin, A. A. J. Biol. Chem., 268, 16689-16695 (1994)). An aliquot of extract (300 μg of protein) was incubated with 25nM nM of [ 3 H]-6-[3-(l- adamantyl)-4-methoxy phenyl]-2-naphthalenecarboxylic acid (50 Ci/mmole) or [ 3 H]-tRA (72 Ci/mmole) (New England Nuclear) in the presence or absence of excess unlabeled ligand in 500 μl of binding buffer (lOmM Tris- HC1, 20mM KCl, 5 mM dithiothreitol, 0.5mM phenylmethylsulfonylfluoride, 1 mM EDTA, 0.1% gelatin, and 10% glycerol) at 22 °C for 90 min. At the end of the incubation, free and bound ligand were separated by loading the sample on a Sephadex G-25 (fine mesh) column, 4 cm in height, packed in a disposable glass Pasteur pipette. The column was eluted with binding buffer. The kD and β MAX were determined utilizing Scatchard analysis. (Scatchard, G., Ann NY Acad. Sci. 51, 600-672, (1949)). Preparation of Extract: Nuclear and cytoplasmic extracts were prepared as previously describ- ed. (Ausbel, F.M.,. Brent, R., Kingston, R.E., Moore, D.D., Seidman, J.G., Smith, J.G., and Struhl, K., (Eds.), Current Protocols in Molecular Biology, Volume 2, pp. 12.1.1-12.1.7, 1990)). In brief, cells are harvested, resuspend- ed in a hypotonic buffer of lOmM HEPES, pH 7.9, 1.5mM MgCl 2 , lOmM KCl, 0.2 mM PMSF, 0.5 mM DDT. The cells are then allowed to swell, are disrupted by homogenization and the nuclei harvested therefrom by differential centrifugation. The resultant nuclear extract is then resuspended in a small volume of low-salt buffer (20mM HEPES pH 7.9, 25 % glycerol, 1.5 mM DTT). The salt concentration is then increased in a drop wise fashion to 300 mM and the extracted nuclei dialyzed against 20mM HEPES, pH 7.9. 20 % glycerol, 100 mM KCl, 0.2 mM EDTA, 0.2 mM PMSF and 0.5 mM DTT. The resultant nuclear extract is then aliquoted and stored at -80 °C One tenth volume of 0.3 M HEPES pH 7.9, 1.4M KCl and 0.03M MgC12 is then added to the cytoplasmic extract obtained following isolation of the nuclei, and dialyzed as described for the nuclear extract. Aliquots are also kept frozen at -80°C Preparation of 5-[3H]-6-[3-(l-adamantyl)-4-hydroxy- 5-[ 3 H] -phenyl] -2-naphthalene carboxylic acid. (a) Preparation of methyl-5-bromo-6-[3-f 1 -adamantylV4-methoxy- 5-bromophenyl]-2-naphthalene carboxylate. 5.44 g (13 mmoles) of methyl-6-[3-(l-adamantyl)-4-methoxyphenyl]-2- naphthalenecarboxylate (prepared as described in Example 9 of US 4,717,720) and one liter of dichloromethane were placed in a reactor and under an argon stream. 10.39 g (65 mmoles) of bromine were added and stirred at room temperature for 15 minutes. The reaction medium was then evaporated to dryness. The obtained residue was purified by chromatography on a silica column eluted with dichloromethane and heptane (40-60). After evaporation of the solvents, 5.38 g (72%) of methyl-5-bromo-6-[3-(l- adamantyl)-4-methoxy-5-bromophenyl]-2-naphthalene carboxylate were recovered (melting point 215-6°C). (b) Preparation of 5-bromo-[3-f l-adamantyl -4-methoxy-5- bromophenyl]-2-naphthalene carboxylic acid. 3.5 g (6.1 mmoles) of the compound obtained in (a) were dissolved in 100 ml of methanol and 50 ml of THF was mixed with 12 ml in a methanol medium in the presence of a 5N sodium hydroxide solution and heated at reflux for 2 hours. The reaction mixture was then cooled, acidified with IN hydrochlorhydric acid and extracted using ethylic ether. The organic phase was then separated therefrom, dried over magnesium sulfate, and evaporated. The residue obtained was taken up in a solution of ethylic ether and heptane (10-90), filtered and dried. 3.3 g (96%) of 5-bromo-6-[3-(l-adamantyl)-4- methoxy-5-bromophenyl]-2-naphthalene carboxylic acid with a melting point of 261 °-262°C was recovered. (c) Preparation of 5-[ 3 H]-6-[3-π-adamantylV4-methoxy-5-[ 3 H]- phenyl-2-naphthalene carboxylic acid. 19.1 mg. of 5-bromo-6-[3-(l -adamantyl)-4-methoxy-5-bromophenyl]- 2-naphthalenecarboxylic acid was dissolved in 400 μl of THF. 30 mg of palladium on carbon (10%) catalyst and 50 μl of N-ethyl morpholine were then added successively thereto. The reaction medium was degassed and stirred for 16.5 hours under a tritium stream (14.5 Ci). The catalyst was then filtrated and washed with methanol. The resultant filtrates were then combined and evaporated to yield the tritiated acid. (d) Preparation of 5-[ 3 H]-6-[3-π-adamantylV4-hvdroxy-5-[ 3 H]- pheny]-2-naphthalene carboxylic acid. The tritiated compound obtained in (c) (140 mCi) was then dissolved in 2 ml of DMF. 2 mg of sodium methanethiolate was added and the mixture heated at 100° C for 12 hours. This reaction did not proceed to completion. Accordingly, an additional 2 mg of sodium methanethiolate were added and the mixture reheated to 100°C for 12 hours. DMF was evaporated, and IN hydrochlorhydric acid was added thereto to produce an acidic reaction medium having a pH of 2. The reaction medium was then extracted with ethyl acetate and the organic phase separated therefrom. This organic phase was then dried over magnesium sulfate, and evaporated. The obtained residue was chromatographed on silica by elution with methanol and dichloromethane. The product was rechromatographed on a reverse phase silica by elution with acetonitrile-water-acetic acid. The specific activity thereof was then determined by UV spectrometry and liquid scintillation and found to be 50 Ci/mmole. The purity thereof was assayed by two methods; thin layer chromatography and by HPLC The results were as follows: - thin layer chromatography [Silica RP-18, eluent: acetonitrile- trifluoroacetic acid (98-2)]. Purity > 97.8%. - HPLC (inverted phase, LICHROSPHER RP-18) eluent acetonitrile- water-acetic acid (80-20-0.2). Purity > 97.8%.

Claims: WHAT IS CLAIMED IS: 1. A receptor, with the exception of an RAR type receptor puta- tively involved in apoptosis, which possesses the following characteristics: (i) specifically binds 6-(3-(l-adamantyl)-4-hydroxyphenyl)- 2-naphthoic acid; and (ii) in a competition binding assay using 6-(3-(l -adamantyl)- 4-hydroxyphenyl)-2-naphthoic acid, the binding of such compound to the subject receptor is only minimally displaced by all-trans retinoic acid. 2. The receptor of Claim 1 , which has an approximate molecular mass of about 90 kilodaltons. 3. The receptor of Claim 1 , which is expressed in nuclear and cytoplasmic extracts of MDA-MB-468 cells. 4. The receptor of Claim 1, which is expressed in cytosolic extracts of HL-60R cells. 5. A method of using the receptor of Claim 1 to identify putative ligands that induce apoptosis comprising the following steps: (i) providing a source of said receptor; (ii) contacting said receptor source with 6-(3-( 1 -adamantyl)- 4-hydroxyphenyl)-2-naphthoic acid or a radiolabeled form thereof; (iii) conducting a competition binding assay with a putative apoptosis inducing ligand to determine whether such ligand significantly competes with said 6-(3-(l-adamantyl)-4-hydroxyphenyl)-2-naphthoic acid or a radiolabeled form thereof in binding to said receptor; and (iv) selecting putative ligands that induce apoptosis based on their relative ability to compete with the binding of 6-(3-(l-adamantyl)-4- hydroxyphenyl)-2-naphthoic acid or a radiolabeled form thereof to said receptor. 6. The method of Claim 5, which further includes (v) radiolabeling said selected ligand and using said ligand to assay and/or characterize receptor expression. 7. The method of Claim 5, wherein the putative ligand is an adamantyl containing retinoid compound. 8. The method of Claim 5, wherein said radiolabeled form comprises deuterium, tritium, carbon 13, carbon 14, or iodine 125. 9. The method of Claim 8, wherein said radiolabeled form is mono-, di or poly-isotopically labeled. 10. The method of Claim 8, wherein the radiolabeled form is [ 3 H]- 6-[3-(l-adamantyl)-4-hydroxy-5-[ 3 H]-phenyl]-2-naphthalenecarboxylic acid. 11. The method of Claim 9, wherein the specific activity of said compound is greater than 20 Ci/m mole. 12. The method of Claim 11 , wherein the specific activity of said compound is at least 50 Ci/m mole. 13. An alkyl ester of 6-[3-(-adamantyl)-4-methoxy phenyl] 2- naphthalene carboxylic acid which comprises at least one halogen atom. 14. The compound of Claim 13, which is methyl-5-bromo-6-[3-(l- adamantyl)-4-methoxy-5-bromo-6-[3-( 1 -adamantyl)-4-methoxy-5- bromophenyl]-2-naphthalene carboxylate. 14. The alkyl ester of Claim 13, which is a methyl ester. 16. The alkyl ester of Claim 13, which contains up to five halogen atoms. 17. The alkyl ester of Claim 16, wherein said halogen is bromine. 18. An antibody produced against the receptor of Claim 1. 19. A nucleic acid sequence which encodes the receptor of Claim 1. 20. A method of identifying a DNA encoding another receptor potentially involved in apoptosis comprising using the nucleic acid sequence of Claim 19 as a probe to screen a DNA library and selecting nucleic acid sequences that hybridize thereto under high stringency conditions. 21. The method of Claim 20, wherein the hybridization probe is used to screen a cDNA or genomic library obtained from a mammalian cell line. 22. The method of Claim 21 , wherein said library is derived from a nuclear or cytosolic extract. 23. A method of using a radioisotopically labeled derivative of 6-[3- (l-adamantyl)-4-methoxyphenyl]-2-naphthalene carboxylic acid as a probe comprising contacting an extract obtained from a desired cell line with said radioisotopically labeled derivative to determine whether it expresses a receptor according to Claim 1. 24. A transfected cell line which expresses a nucleic acid sequence encoding the receptor of Claim 1 , and optionally further expresses an RARγ receptor. 25. A method of producing a radioisotopically-labeled compound useful for identifying a receptor potentially involved in apoptosis comprising the following steps: (i) preparing a mono, di- or poly-halogenated alkyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthalene carboxylic acid; (ii) hydrolyzing said halogenated alkyl ester; (iii) reducing the hydrolyzed alkyl ester using a deutrium or tritium containing reducing agent; and (iv) cleaving the methoxy group to produce a phenol compound; wherein said reduction and cleavage steps may be effected in either order. 26. The method of Claim 25, wherein said alkyl ester is a methyl ester of 6-[3-( 1 -adamantyl)-4-methoxyphenyl]-2-naphthalenecarboxylic acid.

Inventors: FONTANA JOSEPH A, NEDONCELLE PHILIPPE, SHROOT BRAHAM, FONTANA, JOSEPH, A., NEDONCELLE, PHILIPPE, SHROOT, BRAHAM
Applicants: CIRD GALDERMA, FONTANA JOSEPH A, NEDONCELLE PHILIPPE, SHROOT BRAHAM, CENTRE INTERNATIONAL DE RECHERCHES DERMATOLOGIQUES GALDERMA, FONTANA, JOSEPH, A., NEDONCELLE, PHILIPPE, SHROOT, BRAHAM
Application year: 1998
Main classification: C07C63
IPC codes: C07C65, C07C69, C07K14, C07K16, C07K17, C12N5, C12N15, C12Q1