MEANS FOR THE MODULATION OF PROCESSES MEDIATED BY RETINOID RECEPTORS AND COMPOUNDS USEFUL THEREFOR

Abstract: In accordance with the present invention, there are provided methods to modulate processes mediated by retinoid receptors, employing high affinity, high specificity ligands for such receptors. In one aspect of the present invention, there are provided ligands which are more selective for the retinoid X receptor than is retinoic acid (i.e., rexoids). In another aspect of the present invention, alternative ligands (other than retinoic acid) have been discovered which are capable of inducing retinoic acid receptor mediated processes. In yet another aspect, methods have been developed for the preparation of such retinoid receptor ligands from readily available compounds.

Description: MEANS FOR THE MODULATION OF PROCESSES MEDIATED BY RETINOID RECEPTORS AND COMPOUNDS USEFUL THEREFOR FIELD OF THE INVENTION The present invention relates to intracellular receptors, and Iigands therefor. In a particular aspect, the present invention, relates to methods for modulating processes mediated by retinoid receptors. BACKGROUND OF THE INVENTION A central problem in eukaryotic molecular biology continues to be the elucidation of molecules and mechanisms that mediate specific gene regulation in response to exogenous inducers such as hormones or growth factors. As part of the scientific attack on this problem, a great deal of work has been done in efforts to identify exogenous inducers which are capable of mediating specific gene regulation. Although much remains to be learned about the specifics of gene regulation, it is known that exogenous inducers modulate gene transcription by acting in concert with intracellular components, including intracellular receptors and discrete DNA sequences known as hormone response elements (HREs) . As additional members of the steroid/thyroid superfamily of receptors are identified, the search for exogenous inducers for such newly discovered receptors (i.e., naturally occurring (or synthetic) inducers) has become an important part of the effort to learn about the specifics of gene regulation. The retinoid members of the steroid/thyroid superfamily of receptors, for example, are responsive to compounds referred to as retinoids, which include retinoic acid, retinol (vitamin A) , and a series of natural and synthetic derivatives which have been found to exert profound effects on development and differentiation in a wide variety of systems. The identification of compounds which interact with retinoid receptors, and thereby affect transcription of genes which are responsive to retinoic acid (or other metabolites of vitamin A) , would be of significant value, e.g. Λ for therapeutic applications. Recently, a retinoic acid dependent transcription factor, referred to as RAR-alpha (retinoic acid receptor- alpha) , has been identified. Subsequently, two additional RAR-related genes have been isolated; thus there are-now at least three different RAR subtypes (alpha, beta and gamma) known to exist in mice and humans. These retinoic acid receptors (RARs) share homology with the superfamily of steroid hormone and thyroid hormone receptors and have been shown to regulate specific gene expression by a similar ligand-dependent mechanism [Umesono et al. , Nature 336: 262 (1988) ] . These RAR subtypes are expressed in distinct patterns throughout development and in the mature organism. More recently, additional novel members of the steroid/thyroid superfamily of receptors have been identified, such as, for example, retinoid X receptor-alpha [RXR-α; see Mangelsdorf et al., in Nature 345: 224-229 (1990)], retinoid X receptor-beta [RXR-β; see Hamada et al., Proc. Natl. Acad. Sci. USA 86: 8289-8293 (1989)], and retinoid X receptor-gamma [RXR~ ; see Mangelsdorf et al., Genes and Development 6:329-344 (1992)]. While these novel receptors are responsive to retinoic acid, the primary exogenous inducer(s) for these receptors have not been identified. Although both RAR and RXR respond to retinoic acid in vivo, the receptors differ in several important aspects. First, RAR and RXR are significantly divergent in primary structure (e.g., the ligand binding domains of RARα and RXRα have only 27% amino acid identity) . These structural differences are reflected in different relative degrees of responsiveness of RAR and RXR to various vitamin A metabolites and synthetic retinoids. In addition, distinctly different patterns of tissue distribution are seen for RAR and RXR. In contrast to the RARs, which are not expressed at high levels in the visceral tissues, RXRα mRNA has been shown to be most abundant in the liver, kidney, lung, muscle and intestine. Finally, response elements have recently been identified in the cellular retinol binding protein type II (CRBPII) and apolipoprotein Al genes which confer responsiveness to RXR, but not RAR. Indeed, RAR has also been recently shown to repress RXR-mediated activation through the CRBPII RXR response element. These data, in conjunction with the observation that both RAR and RXR can activate through the RAR response element of the RAR? promoter, indicate that the two retinoic acid responsive pathways are not simply redundant, but instead manifest a complex interplay. In view of the related, but clearly distinct nature of these receptors, the identification of Iigands which are more selective for the retinoid X receptor than is retinoic acid would be of great value in selectively controlling processes mediated by one or both of these retinoid receptor types. Other information helpful in the understanding and practice of the present invention can be found in commonly assigned, co-pending United States Patent Application Serial Nos. 108,471, filed October 20, 1987 (now issued as United States Patent Number 5,071,773); 276,536, filed November 30, 1988 (now issued as United States Patent Number 4,981,784); 325,240, filed March 17, 1989; 370 r 407, filed June 22, 1989; and 438,757, filed November 16, 1989, all of which are hereby incorporated herein by reference in their entirety. BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, we have developed methods to modulate retinoid receptor mediated processes, employing high affinity, high specificity Iigands for such receptors. In a particular aspect of the present invention, there are provided Iigands which are high affinity, high specificity Iigands for retinoid receptors. Thus, in one aspect of the present invention, there are provided Iigands which are more selective for the retinoid X receptor than is all- trans-retinoic acid. In another aspect of the present invention, we have discovered alternative Iigands (other than all-trans-retinoic acid) which are capable of inducing retinoic acid receptor mediated processes. In yet another aspect of the present invetion, we have developed methods for the preparation of such retinoid receptor Iigands from readily available retinoid compounds. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a transactivation profile of various HPLC fractions obtained from retinoic acid (RA)-treated S2 cells. Figure 2a is a comparison of the transactivation profile of all-trans-retinoic acid (RA) on RAR-alpha and RXR-alpha. Figure 2b is a similar comparison to that shown in Figure 2a, employing HPLC fraction 18 (instead of RA) . Figure 3 presents several activation profiles for analysis of RXR-alpha or RAR-alpha activation by various retinoic acid isomers. Panel a. represents experiments done in insect S2 cells, while panels b. and c. represent experiments done in mammalian CV-1 cells. In the figure, closed circles are used to designate 9-cis-retinoic acid, open circles are used for all-trans-retinoic acid, open triangles are used for 13-cis-retinoic acid and open squares are used for 11-cis-retinoic acid. Figure 4 presents the results of saturation binding analysis of 9-cis-retinoic acid. Cell extracts were incubated with increasing concentrations of tritiated retinoid in the absence (total binding) or presence (non¬ specific binding) of 200-fold excess non-tritiated retinoid. Non-specific binding was subtracted from total binding and plotted as specific binding. The data shown in Figure 4a represent specific [ H]-9-cis-retinoic acid binding to RXRα (closed circles) or mock (open circles) eexxttrraaccttss;; oorr ssppeecciiffiicc [[ -H] -all-trat.s-retinoic acid binding to RXRα (open squares) Figure 4b presents a Scatchard analysis, wherein specific 9-cis-retinoic acid binding to RXRα in (a) was transformed by Scatchard analysis and plotted. Linear regression yielded a Kd = 11.7 nM (r=0.86). Figure 5 presents a DNA-cellulose column profile of radiolabelled 9-cis-retinoic acid bound to baculoviruε expressed RXR. In Figure 5a, sample cell extracts containing RXRα protein were labelled with 10 nM [ 3 H]-9-cis- retinoic acid in the absence (open squares) or presence (open circles) of 200-fold excess non-radioactive 9-cis- retinoic acid, and then applied to the DNA-cellulose column. Fall-through radioactivity was monitored until a consistent baseline was established. DNA-binding components were then eluted with a linear salt gradient. The peak radioactive fractions (labelled 1-15) were then subjected to immunoblot analysis using an hRXRα-specific antisera. The peak radioactive fraction (indicated by an arrow) co-migrated exactly with the peak amount of RXRα- specific protein. In Figure 5b, the peak radioactive fraction of the DNA-cellulose column is shown to contain 9-cis-retinoic acid. The peak fraction (arrow in (a) ) was extracted and analyzed on a C 18 column developed with mobile phase G. As shown, 0.95% of the extracted radioactivity co-elutes with authentic 9-cis-retinoic acid (absorbance peak) . Figure 6 is a comparison of the transactivation profile for RXR-alpha in the presence of 9-cis-retinoic acid employing a luciferase reporter containing the retinoid response element derived from either the apolipoprotein Al gene (APOA13) or cellular retinol binding protein, type II (CRBPII) . DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a method for modulating process(es) mediated by retinoid receptors, said method comprising conducting said process(es) in the presence of at least one compound of the structure: Rin z Structure A wherein: unsaturation between carbon atoms C , and- C,,10 has a cis configuration, and one or both sites of unsaturation between carbon atoms C through C optionally have a cis configuration; "Ring" is a cyclic moiety, optionally having one or more substituents thereon; Z is selected from carboxyl (-COOH) , carboxaldehyde (-COH) , hydroxyalkyi [-(CR' 2 ) n -OH, wherein each R' is independently selected from hydrogen or a lower alkyl and n falls in the range of l up to about 4], thioalkyl [-(CR* 2 ) n -SH, wherein R' and n are as defined above] , hydroxyalkyi phosphate [-(CR' 2 ) n -OP(OM) 3 , wherein R' and n are as defined above and M is hydrogen, lower alkyl, or a cationic species such as Na + , Li + , K + , and the like], alkyl ether of a hydroxyalkyi group [-(CR'^-OR' , wherein R' and n are as defined above] , alkyl thioether of a thioalkyl group [-(CR' 2 ) n -SR' , wherein R' and n are as defined above] , esters of hydroxyalkyi groups [-(CR' 2 ) n -0-CO-R* , wherein R' and n are as defined above] , thioesters of hydroxyalkyi group [-(CR' 2 ) n -0-CS-R' , wherein R 1 and n are as defined above] , esters of thioalkyl groups [-(CR' 2 ) n -S-C0-R* , wherein R' and n are as defined above] , thioesters of thioalkyl groups [-(CR* 2 ) n -S-CS-R' , wherein R' and n are as defined above], a inoalkyl [-(CR' 2 ) n -NR* 2 , wherein R' and n are as defined above] , N-acyl aminoalkyl [-(CR , 2 ) n -NR'-CO-R", wherein R' and n are as defined above and R" is a lower alkyl or benzyl] , carbamate [ - ( CR ' 2 ) n -NR ' -CO-OR ' or -(CR l 2 ) n -0-CO-N 1 *,, wherein R 1 and n are as defined above] , and the like; and each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents, and the like; or any two or more of the R groups can be linked to one another to form one or more ring structures. Exemplary R groups in the latter situation are selected from alkylene, oxyalkylene, thioalkylene, and the like. As employed herein, the term "modulate" refers to the ability of a ligand for a member of the steroid/thyroid superfamily to induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control. As employed herein, the phrase "processes mediated by retinoid receptors" refers to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to natural or synthetic retinoids, or natural or synthetic compounds as defined herein (referred to herein as "rexoids" because of the ability of many of the compounds described herein to selectively activate retinoid X receptors) . Modulation of such processes can be accomplished in vitro or in vivo . In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like. Exemplary receptors which are responsive to retinoids, and natural or synthetic compounds as defined herein (i.e., "rexoids"), include retinoic acid receptor-alpha, retinoic acid receptor-beta, retinoic acid receptor-gamma, and splicing variants encoded by the genes for such receptors; retinoid X receptor-alpha, retinoid X receptor-beta, retinoid X receptor-gamma, and splicing variants encoded by the genes for such receptors; as well as various combinations thereof (i.e., homodimers, homotrimers, heterodimers, heterotrimerε, and the like) , including combinations of such receptors with other members of the steroid/thyroid superfamily of receptors with which the retinoid receptors may interact by forming heterodimers, heterotrimerε, and higher heteromultimers. For example, the retinoic acid receptor-alpha may form a heterodimer with retinoid X receptor-alpha, the retinoic acid receptor-beta may form a heterodimer with retinoid X receptor-alpha, retinoic acid receptor-gamma may form a heterodimer with retinoid X receptor-alpha, retinoid X receptor-alpha may form a heterodimer with thyroid receptor, retinoid X receptor-beta may form a heterodimer with vitamin D receptor, retinoid X receptor-gamma may form a heterodimer with retinoic acid receptor-alpha, and the like. As employed herein, the phrase "members of the steroid/thyroid superfamily of receptors" (also known as "nuclear receptors" or "intracellular receptors") refers to hormone binding proteins that operate as ligand-dependent transcription factors, including identified members of the steroid/thyroid superfamily of receptors for which specific Iigands have not yet been identified (referred to hereinafter as "orphan receptors") . These hormone binding proteins have the intrinsic ability to bind to specific DNA sequences. Following binding, the transcriptional activity of- target gene (i.e., a gene associated with the specific DNA sequence) is modulated as a function of the ligand bound to the receptor. The DNA-binding domains of all of these nuclear receptors are related, consisting of 66-68 amino acid residues, and possessing about 20 invariant amino acid residues, including nine cysteines. A member of the superfamily can be identified as a protein which contains the above-mentioned invariant amino acid residues, which are part of the DNA-binding domain of such known steroid receptors as the human glucocorticoid receptor (amino acids 421-486) , the estrogen receptor (amino acids 185-250) , the mineralocorticoid receptor (amino acids 603-668) , the human retinoic acid receptor (amino acids 88-153) . The highly conserved amino acids of the DNA-binding domain of members of the superfamily are as follows: Cys - X - X - Cys - X - X - Asp* - X - Ala* - X - Gly* - X - Tyr* - X - X - X - X - Cys - X - X - Cys - Lys* - X - Phe - Phe - X - Arg* - X - X - X - X - X - X - X - X - X - (X - X -) Cys - X - X - X - X - X - (X - X - X -) Cys - X - X - X - Lys - X - X - Arg - X - X - Cys - X - X - Cys - Arg* - X - X - Lys* - Cys - X - X - X - Gly* - Met (SEQ ID No 1) ; wherein X designates non-conserved amino acids within the DNA-binding domain; the amino acid residues denoted with an asterisk are residues that are almost universally conserved, but for which variations have been found in some identified hormone receptors; and the residues enclosed in parenthesis are optional residues (thus, the DNA-binding domain is a minimum of 66 amino acids in length, but can contain several additional residues) . Exemplary members of the steroid/thyroid superfamily of receptors include steroid receptors such as glucocorticoid receptor, mineralocorticoid receptor, progesterone receptor, androgen receptor, vitamin D 3 receptor, and the like; plus retinoid receptors, such as RARα, RKRβ, RAR , and the like, plus RXRα, RXRβ, RXR , and the like; thyroid receptors, such as TRα, TR?, and the like; as well as other gene products which, by their structure and properties, are considered to be members of the superfamily, as defined hereinabove. Examples of orphan receptors include HNF4 [see, for example, Sladek et al., in Genes & Development 4_: 2353-2365 (1990)], the COUP family of receptors [see, for example, Miyajima et al., in Nucleic Acids Research JL6: 11057-11074 (1988) , Wang et al., in Nature 340: 163-166 (1989)], COUP-like receptors and COUP homologs, εuch as those described by Mlodzik et al., in Cell jjj): 211-224 (1990) and Ladias et al., in Science 251: 561-565 (1991) , the ultraspiracle receptor [εee, for example, Oro et al., in Nature 347: 298-301 (1990)], and the like. Processes capable of being modulated by retinoid receptors, in accordance with the present invention, include in vitro cellular differentiation and proliferation, in vitro proliferation of melanoma cell lines, in vitro differentiation of mouse teratocarcinoma cells (F9 cells) , in vitro differentiation of human epidermal keratinocytes, limb morphogenesis, regulation of cellular retinol binding protein (CRBP) , and the like. As readily recognized by those of skill in the art, the availability of Iigands for the retinoid X receptor makes it possible, for the first time, to carry out assays for the identification of antagonists for said receptor. Processes capable of being modulated by retinoid receptors, in accordance with the present invention, also include the in vivo modulation of lipid metabolism, in vivo modulation of skin-related processes (e.g., acne, aging, wrinkling, skin cancer, and the like) , in vivo modulation of malignant cell development, such as occurs, for example, in acute promyelocytic leukemia, testicular cancer, lung cancer, and the like. The ability of compoundε of the invention to modulate such processes is evidenced in a number of ways. See, for example, Figure 6 where the ability of RXR-alpha, in the presence of ligand therefor (e.g., 9-ci.≡.-retinoic acid) is shown to exert a strong effect on the expression of genes under the control of regulatory elements of apolipoprotein Al. Similarly, studies with model systems for a variety of disease states (e.g., differentiation of HL60 cells as a model for acute promyelocytic- leukemia, proliferation of melanoma cell lines as a model for skin cancer, differentiation of keratinocytes as a model for non-malignant skin disorders, and the like) , as set forth in the Examples, demonstrate the ability of retinoid receptors, in the presence of ligand therefor, e.g., 9-cis-retinoic acid, to exert a strong effect on such disease states. Such in vivo applications of the invention process may allow the modulation of various biological processes with reduced occurrence of undesirable side effects, and the like. In vivo applications of the invention process(es) (and compositions) can be employed with a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like. As employed herein, the term "alkyl" refers to "lower alkyl", i.e., alkyl moieties having in the range of 1 up to about 4 carbon atoms, i.e., methyl groups, ethyl groups, propyl groups, isopropyl groups, normal-butyl groups, isobutyl groups, sec-butyl groups, tert-butyl groups, and the like. Cyclic moieties contemplated as part of the compounds employed in the practice of the present invention include 5-, 6-, and 7-membered carbocyclic, heterocyclic aromatic or heteroaromatic rings. Included in this definition, for example, are optionally substituted saturated, mono-unsaturated or polyunsaturated carbocyclic species, such as, for example, cyclopentane, cyclopentene, cyclohexane, cyclohex-2-ene, cyclohex-3-ene, cyclohex-4-ene, and cyclohex-5-ene isomers, and 2,4-, 2,5-, and 3,5-cyclohexadiene variantε thereof. Examples of heterocyclic species contemplated as part of the compounds employed in the practice of the present invention include dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dihydropyran, tetrahydropyran, dihydrothiopyran, tetrahydrothiopyran, piperidine, pyrrolidine, and the like, as well as derivatives thereof. Examples of aromatic or heteroaromatic species contemplated as part of the rexoid compounds of the present invention include phenyl, tolyl, xylyl, mesityl, benzyl, pyridyl, thiophenyl, furanyl, and the like, aε well aε derivatives thereof. Preferred cyclic moieties are typically geminally di-substituted, mono-unsaturated specieε. Preεently preferred geminally di-substituted, mono-unsaturated cyclic moieties are the 1,1,5-trisubstituted cyclohex-5-ene structure of naturally occurring retinoic acid (i.e., the ring structure of ?-ionone; the position of the substituentε on the ring are deεignated employing the traditional retinoic acid numbering convention for the ring structure of yff-ionone) , as well as the 1,1,4,5-tri- substituted cyclohex-5-ene structure provided by hydroxy- or keto-substituted derivativeε of the traditional ff-ionone structure. Compounds contemplated for use in the practice of the present invention include compounds having the structure: Ring Structure A wherein: unsaturation between carbon atoms C 9 and C10 has a cis configuration, and one or both sites of unsaturation between carbon atoms C 11 through C14 optionally have a cis configuration; "Ring" is a cyclic moiety; Z is selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioesters of hydroxyalkyi group, esters of thioalkyl groups, thioesters of thioalkyl groups, aminoalkyl, N-acyl aminoalkyl, carbamate, and the like; and R on each of C, C , C, C , C , C , C , or C 14 is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z subεtituents; or any two or more of the R groups can be linked to one another to form one or more ring structures. Presently preferred compounds which are contemplated by the above generic structure include 9-cis-retinoic acid, as well as novel derivatives thereof such as 9-phenyl-9-cis-retinoic acid, 4-hydroxy-9-cis- retinoic acid, 4-keto-9-cis-retinoic acid, and the like. In another preferred embodiment of the present 9 13 invention, the substituents on C and C are methyl; yet another preferred embodiment, the substituentε on two or 7 8 9 10 11 more of the side chain carbons (i.e., C , C , C , C , C , C , C , or C ) can be linked together to form a ring β 11 structure. For example, the subεtituents on C and C can be linked together to form a structure having a constrained 9-cis double bond (i.e., a 9-ciε locked rexoid derivative) , aε followε: Structure I wherein: X is -[(CR 2 ) χ -X'-(CR 2 ) y ]-, X' is selected from -0-, carbonyl (>CO) , -S-, -S(O)-, -S(0) 2 -, thiocarbonyl (>CS) , -NR"-, or -CR 2 -, R, Ring and Z are as defined above, R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl (-CO-O-alkyl) ; x is 0, 1 or 2, y is 0, 1, or 2, and x + y <2. Such compounds include cyclopentene derivatives, cyclohexene derivatives, cycloheptene derivatives, dihydrofuran derivatives, dihydropyrrole derivatives, and 8 11 the like, wherein the cyclic structure linking C and C serves to prevent isomerization of the cis double bond between C and C . Especially preferred derivatives of structure I are those where Z is a carboxyl group, and Ring is a ?-ionone-like species having the εtructure: ff-ionone ring structure wherein : each R is independently defined as provided above; any one of C 2, C3, or C4 can be replaced with -0-, carbonyl (>C0) , -S-, -S(0)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; wherein R" is as defined above; and said cyclic moiety exists as the saturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated isomer; the 2,4-, 2,5-, or 3,5-diene derivative thereof; or an aromatic derivative thereof. Especially preferred species for use in the practice of the present invention are derivatives of structure I where Z is a carboxyl group, and Ring is a 1,1,5-trisubstituted cyclohex-5-ene structure or a 1,1,4,5-tetrasubstituted cyclohex—5-ene structure. Similarly, the substituents on C and C can be linked together to form a structure having a constrained 9, 11-di-cis configuration (i.e., a 9-cis locked rexoid derivative), as follows: Structure II wherein: X, X', R, R", Z, Ring, x and y are as defined above. Such compounds include cyclopentene derivatives, cyclohexene derivatives, cycloheptene derivatives, dihydrofuran derivatives, dihydropyrrole derivatives, and 10 ,13 the like, wherein the cyclic structure linking C and C serveε to hinder iεomerization of the cis double bond 9 10 . . . between C and C , and prevent isomerization of the cis 11 ,12 double bond between C and C Especially preferred derivatives of Structure II are those where Z iε a carboxyl group, and the Ring iε a 1,1,5-triεubεtituted cyclohex-5-ene εtructure or a 1,1,4,5- tetrasubstituted cyclohex-5-ene εtructure. 8 Similarly, at leaεt two of the εubstituents on C , c 1 \ ,14 and/or C can be linked together to form a structure having a constrained 9, 13-di-cis configuration (i.e., a 9-cis locked rexoid derivative) , shown below aε Structure III: Structure III wherein: one A is X and the other A is X' , and X, X 1 , R, R", Z, Ring, x and y are as defined above. Those of skill in the art recognize that the junction between the two bridging groups (A) can only occur through an atom with a valence of three or four (i.e., through carbon or nitrogen) , so as to accomodate the bonds required to link the fused rings together. Similarly, at least two of the subεtituents on C , C 11, and/or C14 can be li.nked together, and further linked to C of Ring, or to a subεtituent on C to form a εtructure having a conεtrained 9, 13-di-cis configuration (i.e., a 9-cis locked rexoid derivative) , shown below as Structure IV: Structure IV wherein: one A is X and the other A is X' , B is X 1 , and X, X', R, R", Z, Ring, x and y are as defined above. As noted above with respect to Structure III, those of skill in the art recognize that the junction(s) between the bridging groups (A) and (B) can only occur through an atom with a valence of three or four (i.e., through carbon or nitrogen), εo as to accomodate the bondε required to link the fused rings together. Such compounds include cyclopentene derivatives, cyclohexene derivatives, cycloheptene derivatives, dihydrofuran derivatives, dihydropyrrole derivatives, and the like, wherein the cyclic structures linking C , C and/or C serves to prevent isomerization of the cis double bonds at carbon 9 and carbon 13. Especially preferred derivatives of Structures III and IV are those where Z is a carboxyl group, and Ring is a 1 ,1,5-trisubstituted cyclohex-5-ene structure or a 1,1,4,5-tetrasubstituted cyclohex-5-ene structure. Similarly, the εubεtituents on C and C can be linked together to form a structure having a constrained 9-cis double bond (i.e., a 9-cis locked rexoid derivative), as follows: Structure V wherein: X" is -[(CR 2 ) a -X'-(CR 2 ) b ]~, X', R, R", Ring and Z are as defined above, a is 0, 1, 2, 3 or 4, b is 0, 1, 2, 3, or 4, and a + b is >2, but <4. Such compounds include cyclopentene derivatives, cyclohexene derivatives, cycloheptene derivatives, dihydrofuran derivatives, dihydropyrrole derivatives, and the like, wherein the cyclic structure linking C and C serves to prevent isomerization of the cis double bond between C and C . Especially preferred derivatives of Structure V are those where Z is a carboxyl group, and Ring is a 1,1,5-trisubstituted cyclohex-5-ene εtructure or a 1,1,4,5- tetrasubεtituted cyclohex-5-ene structure. Similarly, the subεtituentε on C 7 and C 9 can be linked together, and the εubstituents on C and C can be linked together to form a structure having a constrained 9-cis double bond (i.e., a 9-ciε locked rexoid derivative), as follows: Structure VI wherein: Y is -[(CR 2 ) c -X'-(CR 2 ) d ]-, X 1 , R, R", Ring and Z are as defined above, c iε 0, 1, 2 or 3, d iε 0, 1, 2 or 3, and c + d >1, but <3. Such compoundε include cyclopentene derivativeε, cyclohexene derivatives, cycloheptene derivatives, dihydrofuran derivatives, dihydropyrrole derivatives, and the like, wherein the cyclic structures linking C and C , and C and C serve to prevent isomerization of the cis double bond between C 9 and C10. Especially preferred derivatives of Structure VI are those where Z is a carboxyl group, and Ring is a 1,1,5-trisubstituted cyclohex-5-ene structure or a 1,1,4,5- tetrasubstituted cyclohex-5-ene εtructure. Similarly, the substituents on C 9 and C10 can be linked together to form a structure having a constrained C-9 double bond (i.e., a 9-cis locked rexoid derivative), aε followε: Structure VII wherein: X' * ' is X" or an unsaturated linking group having the εtructure: -[Q = CR - J]-, wherein Q is -N= or -CR=, and J is -CR=CR-, -N=CR-, -CR=N-, -0-, -S-, or -NR"-, . 9 10 thereby incorporating C and C of the rexoid compound into an aromatic (or pseudo-aromatic) ring, and X', X", R, R", Ring, Z, a and b are as defined above. Such compounds include cyclohexene derivatives, cycloheptene derivativeε, benzene derivatives, pyridine derivatives, furan derivatives, thiophene derivatives, pyrrole derivatives, oxazole derivatives, thiazole derivatives, imidazole derivatives, pyrazole derivatives, 9 10 and the like, wherein the cyclic structure linking C and C serves to prevent isomerization of the C 9-C10 double bond; however, rotation about the 8-9 and/or 10-11 εingle bonds can εtill occur. Especially preferred derivatives of Structure VII are those where Z is a carboxyl group, and Ring is a 1,1,5-trisubstituted cyclohex-5-ene structure or a 1,1,4,5- tetrasubstituted cyclohex-5-ene structure. In addition to the structures set forth above, those of skill in the art can readily identify additional means to constrain the basic cis-configuration containing rexoid compounds employed in the practice of the present invention. In accordance with a preferred embodiment of the present invention, the cyclic moiety has the ?-ionone structure set forth above. Especially preferred are the 1, 1, 5-trisubstituted cyclohex-5-ene structure (characteristic of ?-ionone) as well as the closely related 1,1,4,5-tetrasubstituted cyclohex-5-ene εtructure from which many rexoid compoundε according to the present invention can be prepared. In accordance with a particularly preferred embodiment of the present invention, the compounds employed in the invention process are selected from 9-cis-retinoic acid and derivatives thereof as contemplated by Structure A set forth above, as well aε 9-ciε-locked derivativeε of retinoic acid aε set forth in Structures I-VII above. Exa pleε of specific compounds contemplated for use in the practice of the present invention are compounds wherein Z is carboxy, Ring is the 1,1,5-trisubεtituted cyclohex-5-ene structure charateristic of ?-ionone (or the closely related 1,1,4,5-tetrasubstituted cyclohex-5-ene) , and having a side chain structure(s) as described above for Structures I-VII. "Rexoid" derivatives as described above can be prepared employing a variety of synthetic methods, which are readily available (and well known) to those of skill in the art. See, for example, the methods described in Chemistry and Biology of Synthetic Retinoids., Dawson and Okamura, edε., CRC Press, Inc. (1990), especially Chapter 4, by Ito (found at pages 78-97) , and Chapter 9, by de Lera et al. (found at pages 202-227) can readily be adapted for the preparation of the compounds described herein. The contents of this publication are hereby incorporated by reference herein. See also Asato et al. , J. Am. Chem. Soc. 108: 5032 (1986); Sheveε et al. , J. Am. Chem. Soc. 108: 6440 (1986); Akita et al. , J. Am. Chem. Soc. 102: 6370 (1980) ; Derguini and Nakaniεhi, Photobiochem. and Photobiophyε. JL3.: 259 (1986) , the entire contentε of each of which is hereby incorporated by reference herein. In accordance with another embodiment of the present invention, there is provided a method for modulating processes mediated by retinoid receptors, said method comprising conducting said process in the presence of: (a) at least one compound of the structure: Ring wherein: each site of unsaturation in the side chain comprising carbon atoms C 7 through C14 has a trans configuration; "Ring", Z, and R are aε previously described, and (b) a cis/tranε isomerase capable of converting at least the 9-double bond from the trans configuration to the cis-configuration. As employed herein, the term "cis /trans isomerase" refers to enzymes which promote a change of geometrical configuration at a double bond. Examples of such enzymes include maleate isomerase, maleylacetoacetate isomerase, retinal isomerase, maleylpyruvate isomerase, linoleate isomerase, furylfuramide isomeraεe, and the like. In accordance with yet another embodiment of the preεent invention, there iε provided a method to produce compound(s) of the structure: . » 8 ' C R A / ■ C ,0 R Ring wherein: unsaturation between carbon atoms C and C 10 has a ciε configuration, and one or both εiteε of unεaturation between carbon atomε C 11 through C14 optionally have a cis configuration; "Ring" is a cyclic moiety; Z is selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esterε of hydroxyalkyi groups, thioeεters of hydroxyalkyi group, esterε of thioalkyl groupε, thioesters of thioalkyl groups, aminoalkyl, N-acyl aminoalkyl, carbamate, and the like; and each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z subεtituentε; from the correεponding all-trans configuration material, said method comprising contacting said all-trans configuration material with a cis/trans isomerase under isomerization conditions. In accordance with still another embodiment of the present invention, there are provided novel compositions comprising compound(s) of Structure A (excluding previously identified compounds such as retinoic acid as well as constrained compounds selected from Structures I - VII, as set forth above. Examples of such compounds include 9-phenyl-9-cis-retinoic acid, 4-hydroxy-9-cis-retinoic acid, 4-keto-9-cis-retinoic acid, and the like. Presently preferred compounds are those wherein Z is carboxyl and Ring is a 1,1,5-trisubstituted cyclohex-5-ene structure or a 1,1,4,5-tetrasubstituted cyclohex-5-ene structure. The invention compounds can be employed for both in vitro and in vivo applications. For in vivo applications, the invention compounds can be incorporated into a pharmaceutically acceptable formulation for administration. Those of skill in the art can readily determine suitable dosage levels when the invention compounds are so used. As employed herein, the phrase "suitable doεage levelε" refers to levels of compound sufficient to provide circulating concentrations high enough to effect activation of retinoid receptor(s) . Such a concentration typically falls in the range of about 10 nM up to 2 μM; with concentrations in the range of about 100 nM up to 200 nM being preferred. In accordance with a particular embodiment of the present invention, compositionε compriεing at least one 9-cis-retinoic acid-like compound (as described above) , and a pharmaceutically acceptable carrier are contemplated. Exemplary pharmaceutically acceptable carriers include carriers suitable for oral, intravenous, subcutaneous, intramuscular, intracutaneous, and the like administration. Administration in the form of creams, lotions, tablets, dispersible powders, granules, syrups, elixirs, sterile aqueous or non-aqueous solutions, suspensions or emulsions, and the like, is contemplated. For the preparation of oral liquids, suitable carriers include emulsions, solutions, suspensions, syrupε, and the like, optionally containing additives such as wetting agents, emulεifying and suspending agents, sweetening, flavoring and perfuming agents, and the like. For the preparation of fluids for parenteral adminiεtration, suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous εolventε or vehicleε are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use. The invention will now be deεcribed in greater detail by reference to the following non-limiting exampleε. EXAMPLES Example 1 Identification of Compoundfs) that Activate RXR In order to acertain if retinoic acid can be converted to a product that binds directly to RXR, thereby resulting in modulation of transcription, a strategy was developed to identify retinoic acid metabolites that might modulate the transcriptional properties of RXR. The identification of any such active metabolite would allow one to further determine whether this metabolite was capable of directly binding to the receptor protein. Accordingly, the Drosophila melanogaster Schneider cell line (S2) was incubated with or without all-trans-retinoic acid (RA) for a period of 24 hours. Prior to the addition of retinoic acid, Drosophila melanogaster Schneider cell line (S2) cells were grown in Schneider Drosophila medium (GIBCO) supplemented with penicillin, streptomycin and 12% heat inactivated FCS (Irvine Scientific) . One hundred tissue culture flasks (75 cm 2 ) were set up with 10 7 cells and 12 ml of medium/flask. Twenty four hours later, either all-t.ra.ns- retmoic acid (or ethanol solvent control) was added to each flask to a final concentration of 5 x 10 M in reduced light conditions. Cells were harvested 24 hourε later by centrifugation for 5 minutes at 800 g. Cells were washed twice with PBS and the resultant pellets were frozen at -80°C until extraction. In parallel, CV-1 cells were set up on 64 tissue culture dishes (150 mm) at 2 x 10 cells and 25 ml of medium/dish. Cells were treated with retinoic acid and harvested as with the S2 cells except that the CV-1 cells (which are adherent) were washed in their dishes with PBS and scraped with a rubber policeman prior to centrifugation and freezing. Following incubation, the cell pellets were collected, organically extracted and chromatographically fractionated by HPLC. The various HPLC fractions were assayed for their ability to produce a ligand dependent increase in tranεcriptional activity mediated by RXR. This aεsay syεtem involveε transfecting cells with the cDNA for the RXR receptor and a luciferase reporter molecule which iε under control of a promoter containing a RXR response element (RXRE) [see Mangelsdorf et al., Cell 66: 555 (1991) ] . The addition of a ligand capable of activating RXR results in an increase in luciferaεe activity. Schneider cellε, CV-1 cellε and mouεe tissues were extracted as described by C. Thaller and G. Eichele in Nature Vol. 327:625 (1987). Mouse tissue was used to determine if any RXR ligand is present in vivo . In the case of tissue extractions, 2.10 dpm internal standard [11, 12- H]-all-trans-retinoic acid (New England Nuclear) or 9-cis-retinoic acid (generated by isomerization with light) were added to the homogenate. Extractε were fractionated on a Waterε Novapak 300 mm C 18 analytical column at a flow rate of 1 ml min " . The mobile phase (G) was a 1:1 mixture of: A [CH 3 CN/CH 3 OH/2% aqueous CH 3 C00H (3:1:1)] and E [CH 3 CN/CH 3 OH/2% aqueous CH 3 C00H (11:3:10)]. Other mobile phases used have the following compositions: C: CH 3 CN/CH 3 OH/H 2 0/CH 3 COOH (80:10:10:1), H: mix CH 3 OH/10 mM ammonium acetate (9:1) with equal volume of CH 3 OH/10 mM ammonium acetate (3:1). Methyl esters of retinoic acid isomers and/or metabolites contained in the HPLC fractions were generated as described in Wedden et al. [Meth. Enzymol. 190:201 (1990) ] . Reference standards used were from Aldrich, Sigma or kindly provided by Hoffmann-LaRoche. Authentic 9-cis- retinol, 9-cis-retinoic acid and 9-cis-methylretinoate were either synthesized from 9-cis-retinal [see E.J. Corey et al., J. Am. Chem. Soc. 9-0.:5616 (1968); C.D.B. Bridges & R.A. Alvares (Meth. Enzymol. 8JL:463 (1982)] or generated by photoiεomerization of the all-trans iεomer followed by fractionation of the resulting isomers by HPLC. Photoisomerization of all-trans-retinoic acid iε carried out employing εtandard iεomerization techniques which are well known to those of skill in the art. For example, retinoic acid can be dissolved in a polar organic solvent such as ethanol, placed in a quartz cuvette, and irradiated with a variety of wavelengths of light (such as luorescent light) . Temperature at which irradiation is carried out is not critical; accordingly, irradiation can be carried out at room temperature. Irradiation time is also not critical; typical irradiation times are in the range of about 0.5-2 hours. The various HPLC fractions were diluted 1:100 and assayed for their ability to modulate the transcriptional properties of RXR. Cotransfection Assay in CV-1 Cells A monkey kidney cell line, CV-1, was used in the cis-trans assay. Cells were transfected with two DNA transfection vectors. The trans-vector allowed efficient production of retinoid receptor (e.g., RAR or RXR) in theεe cells, which do not normally express these receptors. The cis-vector contains an easily assayable gene, in thiε caεe the firefly luci erase, coupled to a retinoid-responεive promoter. Addition of retinoic acid or an appropriate synthetic retinoid reεultε in the formation of a retinoid- receptor complex that activates the luciferase gene, causing light to be emitted from cell extracts. The level of luciferase activity iε directly proportional to the effectiveness of the retinoid-receptor complex in activating gene expression. This sensitive and reproducible cotransfection approach permits the identification of retinoids that interact with the different receptor isoforms. Cellε were cultured in DMEM supplemented with 10% charcoal resin-stripped fetal bovine serum, and experiments were conducted in 96-well plates. The plasmids were transiently tranεfected by the calcium phoεphate method [U eεono and Evans, Cell -57:1139-1146 (1989); Berger et al., J. Steroid Biochem. Molec. Biol. 4.1:733-738 (1992)] by using 10 ng of a pRS (Rous sarcoma virus promoter) receptor-expresεion plaεmid vector, 50 ng of the reporter luciferase (LUC) plasmid, 50 ng of pRSB-GAL (β-galactosidase) as an internal control, and 90 ng of carrier plasmid pGEM. Cells were transfected for 6 hours and then waεhed to remove the precipitate. The cellε were then incubated for 36 hourε with or without retinoid. After the transfection, all subεequent εteps were performed on a Beckman Bio ek Automated Workstation. Cell extracts were prepared as described by Berger et al. supra, then assayed for luciferase and β-galactosidaεe activities. All determinations were performed in triplicate in two independent experiments and were normalized for transfection efficiency by using β-galactosidaεe aε the internal control. Retinoid activity waε normalized relative to that of retinoic acid and is expresεed as potency (EC50) , which is the concentration of retinoid required to produce 50% of the maximal observed response, and efficacy (%) , which is the maximal response observed relative to that of retinoic acid at 10 " M. The receptor expression vectors used in the cotransfection assay have been described previously [pRShRAR-α: Giguere et al. , Nature 330:624-629 (1987); pRShRAR-β and pRShRAR- : Ishikawa et al., Mol. Endocrinol. :837-844 (1990); retinoid X receptor-alpha (RXR-α) [see Mangelsdorf et al. , in Nature 345: 224-229 (1990)], retmoid X receptor-beta (RXR-β) and retinoid X receptor-gamma (RXR-y) [see Mangelsdorf et al. , Genes and Development 6:329-344 (1992)]. A basal reporter plasmid ΔMTV-LUC [Hollenberg and Evans, Cell 55.:899-906 (1988)] containing two copies of the TRE-palindromic reεponεe element 5'-TCAGGTCATGACCTGA-3' [SEQ ID No 2; see Umeεono et al., Nature 336:262-265 (1988)] was used in all transfections for the retinoid receptors. The bacterial expression vector for PET-8c-RAR-α used in the competitive binding assay has been reported [Yang et al. , Proc. Natl. Acad. Sci. USA 88:3559-3563 (1991) ]. Similar expression vectors employing the PET-8c vector system [Studier et al. , Methods in Enzymology 185:60-69 (1990)] were constructed for RAR-β and RAR- - The transactivation profile of RXR-alpha with the various HPLC fractions containing various retinoic acid isomers and/or metabolites is shown in Figure 1. These data reveal two distinct regions of activity, one relatively early (fraction 7) and a second broader region of activity (fractions 16-21) that elutes conεiderably later. The all-trans-retinoic acid coeluteε in fractionε 20 and 21 (Figure 1) and is the major U.V. absorbing material present in the cell extracts. However, the activity profile demonstrates that, in addition to all-fcrans-retinoic acid, there are active components that must be derived from, or induced by, all-trans-retinoic acid that activate RXR. To identify potential compounds that would be as effective or more active than all-trans-retinoic acid, one must take into account not only the activity of the individual fractions, but also their concentrations. All active fractions were therefore reassayed over a broad range of concentrations, taking into account the relative concentrations of the individual fractions. To determine the relative concentrations of the fractions, the following initial asεumptionε were made: 1) the active fractions are retinoic acid metabolites and 2) the molar extinction coefficient of the various active fractions is relatively εimilar (i.e., within a factor of two). This asεumption is supported by values reported in the literature for a large number of retinoids. A comparison of the transactivation profile of all-trans-retinoic acid (i.e., fraction 20) on RAR-alpha and RXR-alpha is shown in Figure 2a. Although the maximal activation (i.e., efficacy) of RAR and RXR with retinoic acid is similar, RAR is more εenεitive by a factor of approximately 10 fold (i.e., 10 fold more potent). In contraεt, analysis of the various fractions produced as describes above demonstrates that fraction 18 is considerably more active on RXR than RAR (see Figure 2b) . These data suggest that a metabolic product present in S2 cells pretreated with retinoic acid is a more potent activator of the RXR subfamily than the RAR subfamily. Example 2 Identification of 9-cis retinoic acid as a tranεactivator of RXR Two observations suggeεt that fraction 18 (peak X, see Fig. 1) is a cellular metabolite of all-trans- retinoic acid. First, extracts of Schneider cells grown in the absence of all-trans-retinoic acid do not exhibit peak X. Second, when cells are exposed to all-trans-retinoic acid, X appears in a time-dependent fashion. Therefore, to chemically identify X, fraction 18 was subjected to chemical derivatization, high performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS) . It was found that upon methylation with diazomethane, the retention time of peak X εhiftε dramatically (i.e., from 10.2 minuteε to 19.5 minutes under the HPLC conditions used) . This indicates that the compound(s) correεponding to peak X haε a free carboxyl group. When methylated X waε analyzed by GC/MS, the electron impact mode revealed that X giveε riεe to a molecular ion at m/z 314, corresponding to that of a retinoic acid methyl eεter. Thiε suggests that X is a stereoisomer of retinoic acid. To determine which isomer X represents, the retention time of X was compared with that of 9-σis-, 11-cis- and 13-cis-retinoic acid. It was found that X coelutes with authentic 9-cis-retinoic acid. Furthermore, the methyl ester of X coelutes with 9-cis- methylretinoate, and when the methyl ester of X is reduced to the alcohol with lithium aluminum hydride, the resulting product coelutes with authentic 9-cis-retinol. For GC/MS analysis, methylated retinoic acid isomers were dissolved in hexane. The sample was injected via a falling needle injector (280°C) into a 30 m x 0.32 mm fused silica DB5 capillary column (J+J scientific) inserted directly into the ion source of a VG Trio-1000 masε spectrometer operating in electron impact mode (70 eV) . The εample was eluted with a temperature gradient (200-300°C, 10°C min "1 ) Finally, the mass spectrum of authentic 9-cis-retinoic acid methyl ester and that of methylated peak X are found to be identical. Taken together these analyεeε establish that peak X representε 9-ci-s-retinoic acid. Although earlier work indicated the preεence of 9-cis-retinol in fish liver, it was not clear whether 9-cis-retinoic acid existed in vivo (i.e., whether 9-cis-retinoic acid is a physiological compound) . To find out if 9-cis-retinoic acid exists in vivo , mouse liver and kidney tisεueε were extracted. Theεe tissues were selected because they contain a broad spectrum of retinoid metabolites and also express RXR. Prior to extraction, radiolabeled 9-σis-retinoic acid was added to the kidney homogenate to serve as an internal standard. Extracts were first fractionated on a reverse phase column (Waters Novo pak 300 mm C 18 analytical column at a flow rate of 1 ml/min) using mobile phase G. Fractions from the kidney extracts containing radioactive internal standard were rechromatographed on a second C 18 column using mobile phaεe H. This procedure gave a small, but distinct abεorbance peak which co-migrated with authentic 9-cis-retinoic acid. Similarly, liver extract was fractionated on a reverse phase column and eluted with mobile phase G. However under the conditions employed, 9-cis-retinoic acid eluted with all-tra-ns-retinol (which is abundantly present in the liver) . To separate these two retinoids, this fraction was methylated with diazomethane and then reanalyzed by HPLC employing mobile phase C. This approach resulted in a distinct peak coeluting with the authentic methyl ester of 9-σis-retinoic acid. To rule out the posεibility that 9-cis-retinoic acid had formed during the extraction procedure from all-trans-retinoic acid, liver tiεεue homogenate waε εpiked with tritiated all-trans-retinoic acid. Subεequent HPLC fractionation revealed that 94% of the radioactivity still reεided in all-trans-retinoic acid, approximately 5% in 13-cis-retinoic acid and 1% or less in 9-ci-s-retinoic acid. Based on peak area integration the concentrations of 9-cis-retinoic acid in liver and kidney are estimated to be ~4 ng, and -4 ng, respectively, per g of wet weight. This indicates that endogenous 9-cis-retinoic acid is not formed from all-trans-retinoic acid during extraction. In conclusion, these experiments establish that 9-cis-retinoic acid is a naturally occurring retinoic acid isomer. Example 3 Transactivation Profile of Retinoid Isomers on RXR and RAR The establishment that peak X represents a stereoisomer of all-trans-retinoic acid suggeεted that the variouε retinoid iεomers may have different retinoid receptor activation profiles. To further analyze the ability of retinoic acid - isomers to modulate the transcriptional properties of RXR-alpha and RAR-alpha, the four major photoisomerε of all-trans-retinoic acid were identified and assayed for the ability to transactivate RXR and RAR. Figure 3 shows the dose response curves for 13-cis-, 11-cis-, 9-cis- and all-trans-retinoic acid for both RAR-alpha and RXR-alpha. Of the four major isomerε of retinoic acid, 9-cis-retinoic acid is seen to be the most potent and efficacious activator of RXR-alpha in both insect S2 cells (see Figure 3A) and mammalian CV-1 cells (see Figure 3B) . The maximal response (EC50 value) is 10 " M and 5 x lθ "8 M, respectively. The observed rank order of potency for the different isomers is the same in both cell lines. 9-cis-retinoic acid is approximately 40 fold more potent as an activator of RXR than 11-cis-, 13 -cis- or all-trans- retinoic acid. These tranεactivation data strongly suggeεt that 9-cis-retinoic acid is an endogenous RXR-alpha activator. In contrast, 9-σϊs-retinoic acid is equipotent to all-fcrans-retinoic acid as an activator of RAR-alpha (Figure 3C) . The EC50 value for 9-cis-retinoic acid on RAR-alpha is 2 x lθ "7 M. 9-cis-retinoic acid is the most potent RXR-alpha ligand to be tested to date. Similarly, transactivation of other isoforms of RXR (i.e., RXR-beta, RXR-gamma) and RAR (i.e., RAR-beta, RAR-gamma) by 9-cis-retinoic acid was also examined. 9-σis-retinoic acid was also found to be a potent activator of these iεoformε aε well, aε shown in Table 1: Table 1 EC 50 * (nM) Receptor All-trans-retinoic Acid 9-cis-retinoic Acid RAR-α 3861 ± 13 327 ± 30 RAR-β 152 ± 12 95 ± 13 RAR- 48 ± 8 61 ± 5 RXR-α 1174 ± 26 255 ± 17 RXR-β 1841 ± 26 218 ± 17 RXR- 1369 ± 26 254 ± 19 *Mean±SEM Example 4 9-cis retinoic acid Binds Directly to RXRs The ability of 9-cis-retinoic acid to transactivate RXR-alpha suggested testing to εee whether 9-σis-retinoic acid waε also capable of binding directly to RXRs. RXR-alpha was expressed in baculovirus and was shown to have biochemical properties that were identical to the mammalian expressed protein. The baculovirus expressed protein had a molecular weight of 51,000, reacted specifically with RXR-alpha antibody and was capable of binding in vitro to DNA sequenceε that have been previously shown to be specific RXR response elements [i.e. CRBPII, see Mangelsdorf et al., Cell .6 . 6:555 (1991); apolipoprotein Al gene, see Rottman et al. , Mol. Cell Biol. 11:3814 (1991) ] . To characterize the ligand binding characteristics of 9-cis-retinoic acid to baculovirus- derived RXR, saturation binding analysis was carried out (see Figure 4) . Radiolabelled 9-cis-retinoic acid binds specifically to RXR-alpha in a saturable manner. Scatchard analysis suggests a single high affinity binding site with a Kd value of 11.7 nM (see Figure 4b) . Under identical binding conditions [ H]-all-trans-retinoic acid did not bind to RXR-alpha (see Figure 4a) . In addition, 9-cis-retinoic acid was also capable of binding specifically to RAR-alpha as a high affinity ligand. 9-cis-retinoic acid did not bind to mock baculovirus extracts (i.e., control extracts from cells that do not express RXRs) . Similarly, binding studies were also carried out with other isoformε of RXR (i.e., RXR-beta, RXR-gamma) , other isoforms of RAR (i.e., RAR-beta, RAR-gam a) , and cellular reinoic acid binding protein (CRABP) with all-trans-retinoic acid and 9-cis-retinoic acid. While all-fcrans-retinoic acid is known to bind to each of these "receptors", 9-cis-retinoic acid was also found to bind to the other isoformε of retinoid receptorε (but not to the cellular retinoic acid binding protein, CRABP) , as shown in Table 2: Table 2 Kd (nM) Receptor All-trans-retinoic Acid 9-cis-retinoic Acid RAR-α 0.4 0.3 RAR-β 0.4 0.2 RAR- 0.2 0.8 RXR-α No binding 1.5 RXR-β No binding 2.1 RXR- No binding 1.9 CRABP 20 >100 The properties of many memberε of the steroid hormone receptor superfamily have been characterized and defined using DNA cellulose chromatography [see, for example, Pike and Hauεεler, Proc. Natl. Acad. Sci. USA .76:5485 (1979) and Pike et al., J. Biol. Chem. 258:1289 (1983)]. Receptorε, such as the VDR, have been εhown in the presence of their cognate ligand to bind to DNA- cellulose [see, for example, Allegretto et al., J. Biol. Chem. 262:1312 (1987)] with high affinity and the ligand- receptor complex elutes with a salt gradient. A DNA- cellulose column profile of the baculovirus expresεed RXR that had been prelabeled with [ H]-9-cis-retinoic acid iε shown in Figure 5. The two different profileε repreεent 1) the total amount of [ H]-9-cis-retinoic acid bound and 2) the level of binding that remainε in the preεence of 200-fold exceεε of cold (i.e. non-labeled 9-cis-retinoic acid) . There iε a peak of radioactivity (marked in the Figure by an arrow) that elutes off the DNA-cellulose column at 0.15 M KC1. This elution profile is similar to that seen with RARα in the presence of [ H]-all-trans- retinoic acid. A 200 fold excess of cold ligand (i.e. non¬ specific) is capable of competing greater than 90% of the total radioactivity bound, demonstrating that the radioactivity in the peak fractions is 9-σis-retinoic acid specifically bound to RXR. The radioactivity eluted off the column was extracted with organic solvent and subjected to HPLC analysis. Inspection of Figure 5b makes it clear that the radioactivity bound to RXR co-chromatographs with authentic 9-cis-retinoic acid. Thiε observation further confirms that [ H]-9-cis-retinoic acid is the species bound to RXR. To demonstrate that the protein contained in the peak fractions is indeed RXR, these fractions (labelled 1- 15 in Figure 5a) were subjected to immunoblot analyεiε uεing an RXRα specific polyclonal antiserum (see Figure 5a, top) . All fractions containing radioactivity diεplay a distinct RXRα band at a M r of 51,000. When a similar experiment was conducted with a baculovirus mock extract, no specific radioactivity was retained on the column. Taken together, theεe data εtrongly suggeεt that 9-cis-retinoic acid is capable of binding specifically to RXR. Protein sampleε were resuspended in 2X sample buffer [Laemelli, Nature Vol. 227:680 (1970)] and boiled for 5 minutes prior to loading onto a 9% SDS polyacrylamide gel. After electrophoretic separation the gels were electroblotted onto nitrocellulose membranes (Scheicher and Schuell) for 8 hours at 30 voltε using a Hoeffer electro- transfer apparatus. Membranes were then incubated in 10% iεopropanol, 10% acetic acid for 15 minuteε, washed 5 minutes in deionized H 2 0 and 5 minutes in T-TBS buffer (10 mM Tris pH 7.5, 150 mM NaCl and 0.5% Triton X-100) . The membranes were blocked in 5% nonfat milk in T-TBS for 1 hour. The remainder of the protocol was adapted from the Amersham ECL (Enhanced Chemiluminescence) Western blotting detection system kit. The primary antibody was a rabbit polyclonal serum raised against a synthetic peptide corresponding to amino acids 214-229 of hRXRα [ liewer et al., Proc. Natl. Acad. Sci. USA 9:1448-1452 (1992)]. The primary antiserum was diluted 1:5000 in T-TBS. The secondary antibody (Donkey anti rabbit IgG conjugated to horseradiεh peroxidaεe, Amerεham) was used at a dilution of 1:2500. Example 5 Effects of topical application of 9-cis-retinoic acid (compared with all-trans-retinoic acid) on horn-filled utriculus εize in the Rhino Mouse All-trans-retinoic acid iε known to influence cell differentiation and exert profound therapeutic benefits in the treatment of keratinization disorders [Elias et al.. Arch. Dermatol. Vol. 117:160-180 (1981)]. Mezick et al. [εee J. Inveεt. Derm. Vol. 83:110-113 (1984)] demonstrated that topical treatment of rhino mice (hr hr) with all-trans-retinoic acid could reduce keratinized pilosebaceous structures (horn-filled utriculus) . This animal teεt model was used to evaluate the "antikeratinizing" effects of 9-cis-retinoic acid. Resultε are summarized in Table 3: Table 3 Pilosebaceous structure size (% red'n) Vehicle Control 178 μm 9-cis-retinoic acid, 0.1% 52 μm (-74%) 0.01% 72 μm (-64%) All-trans-retinoic acid, 0.1% 44 μm (-78%) 0.01% 50 μm (-75%) 9-cis-retinoic acid reduced the mean utriculi diameter after 14 days of topical application. These results demonstrate that topical application of 9-cis-retinoic acid over a 14 day period can reduce keratinized pilosebaceous structures (horn-filled utriculus) in Rhino mouse skin. Reduction in the mean utriculi diameter by 9 -cis-retinoic acid was comparable to that observed with all-trans-retinoic acid. Example 6 Effects of 9-cis-retinoic acid (compared with all-trans-retinoic acid) on differentiation of HL60 cells Retinoids are known to differentiate human promyelocytic leukemia cells. Differentiation of HL60 cells (a model syεte for promyelocytic leukemia) can be asεessed by Nitro Blue Tetrazolium (NBT) dye reduction (superoxide anion generation) and by meaεurement of up- regulation of the gene encoding the β εubunit of the leukocyte adherence receptor, CD18 (J.B.C. vol. 263 No. 27, pp. 13863-13867) . The EC-50 for 9-cis-retinoic acid-mediated differentiation, as determined by NBT after 6 days treatment, was 0.2 μM compared to 2 μM for all-trans-retinoic acid. Maximal effects (efficacies) were comparable, and CD18 was up-regulated by both Iigands. Alpha-interferon potentiated both all-trans-retinoic acid and 9-σis-retinoic acid-mediated differentiation, as determined by NBT. HL60R cells have been shown to be resistant to differentiation by all-trans-retinoic acid, probably related to a mutation in the retinoic acid receptor-alpha gene. This cell line was found to be resistant to differentiation (NBT) by both all-trans-retinoic acid and 9-cis-retinoic acid at concentrations up to 10 μM. 9-cis-retinoic acid effects differentiation of HL60 cells as evidenced by NBT and up-regulation of CD18. Compared with all-trans retinoic acid, 9-cis retinoic acid is more potent with similar efficacy. Example 7 Effects of 9-cis-retinoic acid (compared with all-trans-retinoic acid, on in vitro proliferation of melanoma cell lines All-trans-retinoic acid and several synthetic analogs (retinoids) have been shown to prevent the development of benign and malignant, chemically induced epithelial tumors in vivo [Sporn et al., Fed. Proc. Vol. 35:1332-1338 (1976)]. Lotan et al. (J. Natl. Cancer, Vol. 60:1035-1041, 1978) found that all-trans-retinoic acid inhibited the growth of several tumor cell lines in vitro . In view of these earlier findings, it was of intereεt to evaluate the growth inhibitory propertieε of 9-cis-retinoic acid. 9-cis-retinoic acid inhibited the growth of the murine melanoma cell line Clone M3 in a concentration dependent manner, as follows: % Growth inhibition (Cone added) 1 iM 0.01 uM 9-cis-retinoic acid -85% -49% all-trans-retinoic acid -94% -48% Similarly, 9-cis retinoic acid inhibited the growth of the human primary metastatic melanoma cell line c81-46c in a concentration dependent manner. % Growth inhibition (Cone added ) 1 UM 0.01 UM 9-cis-retinoic acid -45% -28% all-trans-retinoic acid -44% -17% In summary, 9-cis-retinoic acid has been shown to inhibit the in vitro proliferation of murine melanoma cell line Clone M3 and human metastatic melanoma cell line c81-46c in a concentration dependent manner. 9-cis-retinoic acid has an equal inhibitory effect on these cells as compared to all-trans-retinoic acid. Example 8 Effects of 9-cis-retinoic acid (compared with all-trans-retinoic acid) on differentiation of F9 cells Retinoids are known to differentiate mouse teratocarcinoma cells (F9) . Differentiation of F9 cells is specifically associated with irreversible changes in morphology and induction of the biochemical marker alkaline phosphataεe (ALP) and tissue plasminogen activator (tPA) (Biochem. J. Vol. 274:673-678). Both all-trans-retinoic acid and 9-cis-retinoic acid induced differentiation of F9 cells into partial endoderm-like cells as indicated by irreversible changes in cellular morphology. All-trans-retinoic acid waε 40 times more potent than 9-cis-retinoic acid in inducing ALP, maximal reεponεes were similar. The response of tissue plasminogen activator factor was less for 9-cis-retinoic acid than for all-trans-retinoic acid. At a concentration of 1 μM of 9-cis-retinoic acid (or all-trans-retinoic acid) , increased cellular activities of tPA by 0.48±0.05 and 0.80±o.08, respectively were observed. This effect was concentration- dependent. In summary, 9-σis-retinoic acid promoted differentiation of F9 cells as evidenced by changes in morphology and marker enzyme " activities. Compared with all-trans-retinoic acid, 9-cis-retinoic acid was less potent with regard to both enzyme markers. Efficacy was comparable with ALP but indeterminate for tPA. Example 9 Effects of 9-cis-retinoic acid (compared with all-trans- retinoic acid) on differentiation of keratinocvtes Retinoids are known to inhibit squamous cell differentiation of cultured normal human epidermal keratinocytes (NHEK534 cell line) , as judged by morphological alterations and inhibition of induction of transglutaminaεe (Type I) (J. Biol. Chem. Vol. 261:15097, 1986; Lab. Invest. Vol. 56:654, 1987). Both all-trans-retinoic acid and 9-cis-retinoic acid inhibited squamous cell differentiation in a concentration dependent manner as judged by morphological changes and by transglutaminase activity. The EC50s for inhibition of differentiation by all-trans-retinoic acid and 9-σis-retinoic acid were identical (20±2.8 nM) . 9-cis retinoic acid and all-trans-retinoic acid EC50s and potencieε were nearly identical for effects on tranεglutaminaεe activitieε. In summary, like all-trans-retinoic acid, 9-cis-retinoic acid inhibits morphological differentiation of NHEK534 cells and induction of transglutaminase activity. Example 10 Synthesiε of 9-phenyl-9-σis-retinoic acid To a εolution of 44 mg (0.10 mmole) of the following phoεphonate reagent: in THF (0.5 ml) at room temperature was added NaH (60% in oil, 5 mg; 0.13 mmole) and the mixture stirred at that temperature for 10 minutes. To this, 26 mg (0.08 mmole) of the aldehyde: in THF (0.5 ml) was added at room temperature and the mixture allowed to stir for 30 minutes. Aqueous workup in the usual manner (NH A C1 (aq) , H 2 0, brine, MgS0 4 ) gave a mixture of 9-pheny1-9-cis ester and 9-phenyl-9,13-dicis eεter (30 mg, 92%) (the calculated ratio of 9-cis 9,13- dicis = 4:1) . ethyl ester of 9-phenyl-9-cis-retinoic acid: COOEt ethyl ester of 9-phenγl-9.13-dicis-retinoic acid: To a mixture of 9-cis and 9, 13-dicis ester (20 mg, 0.05 mmole) in methanol (0.7 ml) and H 2 0 (0.7 ml) at 25°C waε added KOH (14.3 mg, 0.25 mmole) . Conεequently, the mixture was heated to 70°C for 2 hourε. The reaction was then cooled down to 0°C, diluted with 10 ml of diethyl ether), and acidified with HC1 (0.12M in HC1, 2.17 ml) . Aqueous workup in the usual manner (H 2 0, brine, MgS0 4 ) gave a mixture of 9-cis and 9,13-diciε acid. Flaεh column chromatography (silica, 13% ethyl acetate in benzene) gave pure 9-pheny1-9 -cis retinoic acid (14.5 mg. 100%) . The 1 HNMR spectrum of 9-pheny1-9 -cis retinoic acid is as follows: 1 HNMR (400 mHz) , CDC1 3 ) δ 1.4 - 7.3 (m, 5H, aromatic), 7.20 (dd, J = 16, 12 Hz, 1H, olefinic) , 6.60 (d, J = 16 Hz, 1 H, olefinic) , 6.38 (d, J = 16 Hz, 1 H, olefinic) , 6.25 (d, J = 12 Hz, 1H, olefinic) , 6.15 (d, J = 16 Hz, 1 H, olefinic) , 5.80 (s. 1H, olefinic) , 2.48 (S. 3H, CH 3 1, 2.05 (t. J = 5Hz, 2H, CH 2 ) , 1.79 (s, 3H, CH 3 ) , 1.70 - 1.40 (m, 4H, CH 2 ~CH 2 ) , 1.00 (s, 6H, 2 X CH 3 ) . 9-phenyl-9-cis RA : TLC Rf 0.23 (13% ethyl acetate in Benzene) Example 11 Synthesis of 4-hydroxy-9-cis-retinoic acid To a solution of 9-cis-retinoic acid (51 mg, 0.17 mmole) in 1.4-dioxane (2 ml) was added Se0 2 (19 mg, 0.17 mmole) at 60°C The solution was allowed to stir at that temperature for 3 hours. The reaction mixture was then filtered through a silica bed. The filtrate was concentrated and the reεidue εubjected to flash column chromatography (silica, 75% ether in petroleum ether) to afford 4-0H-9-cis-retinoic acid (21 mg. , 40% yield) , which is characterized as follows: Oil; TLC Rf = 0.25 (silica, 75% ether in petroleum ether); 1 HNMR (400 MHz, CDC1 3 ) δ 7.08 (dd, J = 16, 12 Hz, 1H, olefinic) ; 6.64 (d, J = 16 Hz, 1H, olefinic) , 6.21 (d, J = 16 HZ, 1H, olefinic) , 6.20 (d, J = 16 Hz, 1H, olefinic) ; 6.04 (d, J = 12 Hz, olefinic) , 5.79 (s, 1H, olefinic) , 4.02 (t, J = 5 Hz, 1H, CH-0) , 2.18 (s y 3H, CH 3 ) , 2.02 (s, 3H, CH 3 ) , 1.82 (s, 3H, CH 3 ) , 2.0-1.6 (m, H, CH 2 -CH 2 ) , 1.05, 1.03 (2 X s, 2 X 3H, 2 X CH 3 ) . Example 12 Synthesis of 4-keto-9-σis-retinoic acid To a solution of 4-hydroxy-9-cis-retinoic acid (16 mg, 0.05 mmole) in CH 2 C1 2 (1.5 ml) was added Dess-Martin reagent [see Desε and Martin in J. Org. Chem. 48:4155 (1983)] (42 mg, 0.1 mmole) in one portion at 25°C. After εtirring for 5 minutes, the mixture was diluted with 10 ml of ether and to this was added saturated aqueous NaHC0 3 (5 ml) containing Na 2 S0 3 (55 mg) . The mixture was stirred for 20 minutes to disεolve the εolid and the layers separated. The ether layer was washed with H 2 0 (2 x 5 ml) , brine (5 ml) and dried (MgSO^) . The solvent was recovered under reduced pressure and residue was subjected to flash column chromatography (εilica, 60% ether in Hexane) to give 4- keto-9-cis-retinoic acid (14 mg. 90%) , characterized as follows: TLC rf = 0.6 (silica, 80% ether in hexane); MR (400 mHz, CDC1 3 ) δ 7.05 (dd, J = 16, 12 Hz, 1H, olefinic) , 6.82 (d, J = 16 Hz, 1 H, olefinic) , 6.32 (d, J = 16 Hz, 1H, olefinic) , 6.30 (d, J = 16 Hz, 1H, olefinic) , 6.20 (d, J = 12 Hz, 1H, olefinic) , 5.80 (s, 1H, olefinic) , 2.5 (t, J = 7 Hz, 2H, CH 2 -C0) , 2.31 (ε, 3H, CH 3 ) , 2.01 (s, 3H, CH 3 ) , 1.9 (s, 3H, CH 3 ) , 1.89 (m, 2H, CH 2 ) , 1.20 (ε, 6H, 2 x CH 3 ) . Example 13 Jn vitro evaluation of 9-phenyl-9cis-retinoic acid, 4-hvdroxy-9-cis-retinoic acid and 4-keto-9-cis-retinoic acid The potency and efficacy of the compounds described in Examples 10, 11 and 12 were determined (as described in Example 1—under the heading "Cotranεfection Assay in CV-1 Cells". The resultε are preεented in Table 4: Table 4 While the invention has been described in detail with reference to certain preferred embodiments thereof, it will be understood that modifications and variations are within the spirit and scope of that which is described and claimed. SEQUENCE LISTING SEQ ID NO:l Cys - X - X - Cys - X - X - Asp* - X - Ala* - X Gly* - X - Tyr* - X - X - X - X - Cys - X - X - Cys Lys* - X - Phe - Phe - X - Arg* - X - X - X - X - X X - X - X - X - (X - X -) Cys -X - X - X - X - X - (X X - X -) Cys -X - X - X - Lys - X - X - Arg - X - X Cys - X - X - Cys - Arg* - X - X - Lys* - Cys - X - X X - Gly* - Met SEQ ID NO:2 5'-TCAGGTCATGACCTGA-3'

Claims: That which is claimed is: 1. A method for modulating process (es) mediated by retinoid receptors, said method comprising conducting said process(es) in the presence of at least one compound of the structure: wherein: 9 10 unsaturation between carbon atoms C and C has a cis configuration, and one or both sites of 11 14 unsaturation between carbon atoms C through C optionally have a cis configuration; "Ring" is a cyclic moiety; Z is selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioesters of hydroxyalkyi group, esterε of thioalkyl groups, thioesters of thioalkyl groups, aminoalkyl, N-acyl aminoalkyl, or carbamate; and each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z subεtituents; or any two or more of the R groups can be linked to one another to form one or more ring structures. 2. A method according to claim 1 wherein said retinoid receptor is selected from retinoic acid receptor-alpha, retinoic acid receptor-beta, or retinoic acid receptor-gamma. 3. A method according to claim 1 wherein said retinoid receptor is selected from retinoid X receptor- lpha, retinoid X receptor-beta, or retinoid X receptor-gamma. 4. A method according to claim 1 wherein said procesε iε selected from in vitro cellular differentiation, in vitro cellular proliferation, in vitro proliferation of melanoma cell lines, in vitro differentiation of mouse teratocarcinoma cells (F9 cells) , in vitro differentiation of human epidermal keratinocytes, regulation of cellular retinol binding protein (CRBP) , or in vitro limb morphogenesis. 5. A method according to claim 1 wherein said procesε iε εelected from the in vivo modulation of lipid metaboliεm, in vivo modulation of εkin-related proceεses, or in vivo modulation of malignant cell development. 6. A method according to claim 1 wherein said compound has the structure (I) : Structure I wherein: X is -[(CR 2 ) χ -X'-(CR 2 ) y ]-, X' is εelected from -0-, carbonyl, -S-, -S(O)-, -S(0) 2 -, thiocarbonyl, -NR"-, or -CR 2 -, "Ring" is a cyclic moiety; Z iε selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioesters of hydroxyalkyi group, esterε of thioalkyl groupε, thioeεters of thioalkyl groups, aminoalkyl, N-acyl aminoalkyl, or carbamate; and each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, or amino; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; x is 0, 1 or 2, y is 0, 1, or 2, and x + y <2. 7. A method according to claim 1 wherein said compound has the structure (II) : Structure II wherein: X is -[(CR 2 ) χ -X'-(CR 2 ) y ]-, X' is selected from -O-, carbonyl, -S-, -S(O)-, -S(0) 2 -, thiocarbonyl, -NR"-, or -CR 2 -, "Ring" is a cyclic moiety; Z is selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioeεters of hydroxyalkyi group, esters of thioalkyl groups, thioesterε of thioalkyl groupε, aminoalkyl, N-acyl aminoalkyl, or carba ate; and each R is independently εelected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; x is 0, 1 or 2, y is 0, 1, or 2, and x + y <2. 8. A method according to claim 1 wherein said compound has the structure (III) : Structure III wherein: one A is X and the other A is X' , X is -[(CR 2 ) χ -X'-(CR 2 ) y ]-, X' is selected from -0-, carbonyl, -S-, -S(O)-, -S(0) 2 -, thiocarbonyl, -NR"-, or -CR 2 -, "Ring" is a cyclic moiety; Z is selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioesterε of hydroxyalkyi group, esters of thioalkyl groups, thioesters of thioalkyl groups, aminoalkyl, N-acyl aminoalkyl, or carbamate; and each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z εubεtituentε; R" iε hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; x is 0, 1 or 2, y is 0, 1, or 2, and x + y <2. 9. A method according to claim 1 wherein said compound has the structure (IV) : Structure IV wherein: one A is X and the other A is X* , B is X 1 , X is -[(CR 2 ) χ -X'-(CR 2 ) y ]-, X' is selected from -0-, carbonyl, -S-, -S(O)-, -S(0) 2 -, thiocarbonyl, -NR"-, or -CR 2 -, "Ring" is a cyclic moiety; Z is selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esterε of hydroxyalkyi groups, thioesters of hydroxyalkyi group, esters of thioalkyl groups, thioesters of thioalkyl groups, aminoalkyl, N-acyl aminoalkyl, or carbamate; and each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; x is 0, 1 or 2, y is 0, 1, or 2, and x + y <2. 10. A method according to claim 1 wherein said compound haε the structure (V) : Structure V wherein: X" is -[(CR 2 ) a -X'-(CR 2 ) b ]-, X* is selected from -0-, carbonyl, -S-, -S(0)-, -S(0) 2 -, thiocarbonyl, -NR"-, or -CR 2 -, "Ring" is a cyclic moiety; Z is εelected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioesters of hydroxyalkyi group, esters of thioalkyl groups, thioesters of thioalkyl groups, aminoalkyl, N-acyl aminoalkyl, or carbamate; and each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituentε; R" is hydrogen, halogen, alkyl, hydroxy, or thiol; a is 0, 1, 2, 3 or 4, b is 0, 1, 2, 3, or 4, and a + b is >2 , but <4. 11. A method according to claim 1 wherein said compound has the structure (VI) : Structure VI wherein: Y is -[(CR 2 ) c -X'-(CR 2 ) d ]-, X 1 is selected from -0-, carbonyl, -S-, -S(O)-, -S(0) 2 -, thiocarbonyl, -NR"-, or -CR 2 -, "Ring" is a cyclic moiety; Z is selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioesters of hydroxyalkyi group, esters of thioalkyl groups, thioesterε of thioalkyl groupε, aminoalkyl, N-acyl aminoalkyl, or carbamate; and each R iε independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituentε; R" iε hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; c is 0, 1, 2 or 3, d is 0, 1, 2 or 3, and c + d >1, but <3. 12. A method according to claim 1 wherein said compound has the structure (VII) : Structure VII wherein: X 1 ' ' is X" or an unεaturated linking group having the structure: -[Q = CR - J]-, wherein Q is -N= or -CR=, and J is -CR=CR-, -N=CR-, -CR=N-, -0-, -S-, or -NR"-, thereby incorporating C 9 and C10 of the rexoid compound into an aromatic (or pseudo-aromatic) ring, X" is -[(CR 2 ) a -X'-(CR 2 ) b ]-, X 1 is selected from -0-, carbonyl, -S-, -S(O)-, -S(0) 2 -, thiocarbonyl, -NR"-, or -CR 2 -, "Ring" is a cyclic moiety; Z iε selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioesterε of hydroxyalkyi group, esters of thioalkyl groups, thioesters of thioalkyl groups, aminoalkyl, N-acyl aminoalkyl, or carbamate; and each R iε independently elected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z εubεtituentε; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; a is 0, 1, 2, 3 or 4, b is 0, 1, 2, 3, or 4, and a + b is >2, but <4. 13. A method according to claim 1 wherein Ring has the following structure: wherein: each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z εubεtituentε; any one of C 2, C3, or C4 can be replaced with -0-, carbonyl (>C0) , -S-, -S(0)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; R" iε hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; and εaid cyclic moiety exists as the saturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated isomer, or the 2,4-, 2,5-, or 3,5-diene derivative thereof; or an aromatic derivative thereof. 14. A method according to claim 6 wherein Ring has the following εtructure: wherein: each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; any one of C 2, C3-, or C4 can be replaced with -0-, carbonyl (>C0) , -S-, -S(0)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; and said cyclic moiety existε aε the saturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated isomer, or the 2,4-, 2,5-, or 3,5-diene derivative thereof, or an aromatic derivative thereof. 15. A method according to claim 7 wherein Ring has the following εtructure: wherein: each R iε independently εelected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; any one of C 2, C3, or C4 can be replaced with -o-, carbonyl (>CO) , -S-, -S(O)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; and said cyclic moiety existε aε the εaturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated isomer, or the 2,4-, 2,5-, or 3,5-diene derivative thereof. 16. A method according to claim 8 wherein Ring has the following structure: wherein: each R iε independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; any one of C 2, C3, or C4 can be replaced with -0-, carbonyl (>C0) , -S-, -S(O)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; and said cyclic moiety existε aε the εaturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated iεomer, or the 2,4-, 2,5-, or 3,5-diene derivative thereof; or an aromatic derivative thereof. 17. A method according to claim 9 wherein Ring has the following structure: wherein: each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; any one of C 2, C3, or C4 can be replaced with -0-, carbonyl (>C0) , -S-, -S(O)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; and said cyclic moiety exists as the saturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated iso er, or the 2,4-, 2,5-, or 3,5-diene derivative thereof; or an aromatic derivative thereof. 18. A method according to claim 10 wherein Ring has the following structure: wherein: each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; any one of C 2, C3, or C4 can be replaced with -0-, carbonyl (>C0) , -S-, -S(0)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; and said cyclic moiety exists as the saturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated isomer, or the 2,4-, 2,5-, or 3,5-diene derivative thereof; or an aromatic derivative thereof. 19. A method according to claim 11 wherein Ring has the following structure: 1-2 wherein: each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; any one of C 2, C3, or C4 can be replaced with -0-, carbonyl (>CO) , -S-, -S(O)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; and said cyclic moiety existε as the saturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated isomer, or the 2,4-, 2,5-, or 3,5-diene derivative thereof; or an aromatic derivative thereof. 20. A method according to claim 1 wherein said compound is selected from 9-cis-retinoic acid, 9-phenyl-9-cis-retinoic acid, 4-hydroxy-9-cis-retinoic acid, 4-keto-9-cis-retinoic acid, 9,11-dicis retinoic acid, and 9-cis-locked derivatives of retinoic acid selected from Structures I-VII as set forth in the specification, wherein Z iε carboxyl and Ring iε a ?-ionone or ?-ionone-like species having the εtructure: wherein A 4 is selected from >CH 2 , >C=0 or >C-0H. 21. A method according to claim 1 wherein Ring has four or five carbon atoms and is selected from cyclopentane, cyclopentene, dihydropyran, tetrahydropyran, piperidine, dihydrothiopyran, tetrahydrothiopyran, dihydrofuran, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, or derivatives thereof. 22. A method to modulate processes mediated by retinoid receptors, said method comprising conducting said process in the presence of: (a) at least one compound of the structure: wherein: each site of unsaturation in the side chain comprising carbon atoms C 7 through C14 has a trans configuration; "Ring" is a cyclic moiety; Z is selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioesters of hydroxyalkyi group, esterε of thioalkyl groups, thioesters of thioalkyl groups, aminoalkyl, N-acyl aminoalkyl, carbamate, and the like; and each R is independently εelected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z εubεtituents; and (b) a ciε/trans isomerase capable of converting at least one of the 9-, 11-, or 13-double bonds from the trans configuration to the cis-configuration. 23. A method to produce compound(s) of the structure: wherein: 9 TO unsaturation between carbon atoms C and C has a cis configuration, and one or both sites of unsaturation between carbon atoms C 11 through C14 optionally have a cis configuration; "Ring" is a cyclic moiety; Z is selected from carboxyl, carboxaldehyde, hydroxyalkyi, thioalkyl, hydroxyalkyi phosphate, alkyl ether of a hydroxyalkyi group, alkyl thioether of a thioalkyl group, esters of hydroxyalkyi groups, thioesters of hydroxyalkyi group, esters of thioalkyl groups, thioesterε of thioalkyl groupε, aminoalkyl, N-acyl aminoalkyl, carbamate, and the like; and each R iε independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; from the corresponding all-trans configuration material, said method comprising contacting said all-trans configuration material with a cis/trans isomerase under isomerization conditions. 24. A method according to claim 23 wherein Ring is a cyclohexyl ring having the following structure: wherein: each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; any one of C 2, C3, or C4 can be replaced with -0-, carbonyl (>C0) , -S-, -S(O)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; and said cyclic moiety exists as the saturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated isomer, or the 2,4-, 2,5-, or 3,5-diene derivative thereof. 25. A method according to claim 23 wherein said contacting is carried out in vivo. 26. A method according to claim 25 wherein εaid contacting iε carried out in Schneider cellε. 27. A method according to claim 23 wherein said contacting is carried out in vitro. 28. Composition comprising at least one compound having a structure selected from: Ring Structure A wherein: unsaturation between carbon atoms C 9 and C10 has a cis configuration, and one or both sites of unsaturation between -carbon atoms C through C optionally have a cis configuration; "Ring" is a cyclic moiety, optionally having one or more substituents thereon; Z is selected from carboxyl (-COOH) , carboxaldehyde (-COH) , hydroxyalkyi [-(CR' 2 ) n -OH, wherein each R' is independently selected from hydrogen or a lower alkyl and n falls in the range of 1 up to about 4], thioalkyl [-(CR' 2 ) n -SH, wherein R 1 and n are as defined above] , hydroxyalkyi phosphate [-(CR' 2 ) n -OP(OM) 3 , wherein R 1 and n are as defined above and M is hydrogen, lower alkyl, or a cationic species such as Na + , Li + , K + , and the like] , alkyl ether of a hydroxyalkyi group [-(CR' 2 ) n -OR' , wherein R' and n are as defined above] , alkyl thioether of a thioalkyl group [-(CR'^-SR 1 , wherein R' and n are as defined above] , esters of hydroxyalkyi groups [-(CR' 2 ) n -0-CO-R' , wherein R 1 and n are as defined above] , thioesters of hydroxyalkyi group [-(CR' 2 ) n -0-CS-R* , wherein R' and n are as defined above] , esterε of thioalkyl groups [-(CR' 2 ) n -S-CO-R' , wherein R 1 and n are as defined above] , thioesters of thioalkyl groups [-(CR' 2 ) n -S-CS-R' , wherein R' and n are as defined above], aminoalkyl [-(CR l 2 ) n -NR' 2 , wherein R' and n are as defined above] , N-acyl aminoalkyl [-(CR'^-NR'-CO-R", wherein R 1 and n are as defined above and R" iε a lower alkyl or benzyl] , carba ate [ - ( CR ' 2 ) n -NR * -CO-O ' or -(CR'^-O-CO-NR' j , wherein R 1 and n are as defined above] ; and each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents, with the proviso thatstructure A is not 9-cis-retinoic acid; or any two or more of the R groups can be linked to one another to form one or more ring structureε; Structure I; wherein: "Ring", Z and R are aε defined above; X iε -[(CR 2 ) χ -X'-(CR 2 ) y ]-, X 1 iε εelected from -0-, carbonyl, -S-, -S(O)-, -S(0) 2 -, thiocarbonyl, -NR"-, or -CR 2 -, R" iε hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; x is 0, 1 or 2, y is 0, 1, or 2, and x + y <2; 80 Structure II ; wherein: X, X 1 , R, R", Z, Ring, x and y are as defined above; 95 Structure III wherein : one A is X and the other A is X' , and X, X 1 , R, R", Z, Ring, x and y are as defined above; 110 Structure IV; wherein: one A iε X and the other A iε X 1 , B iε X• , and X, X 1 , R, R", Z, Ring, x and y are aε 115 defined above; Structure V; 125 wherein: X" is -[(CR 2 ) a -X'-(CR 2 ) b ]-, X 1 , R., R", Ring and Z are as defined above, a is 0, 1, 2, 3 or 4, b is 0, 1, 2, 3, or 4, and 130 a + b is >2, but <4; 140 Structure VI; wherein: Y is -[(CR 2 ) c -X'-(CR 2 ) d ]-, X 1 , R, R", Ring and Z are as defined above, 145 c is 0, 1, 2 or 3, d is 0, 1, 2 or 3, and c + d >1, but <3; and Structure VII wherein : X' ' * is X" or an unsaturated linking group 160 having the structure: -[Q = CR - J]-, wherein Q is -N= or -CR=, and J is -CR=CR-, -N=CR-, -CR=N-, -0-, -S-, or -NR"-, thereby incorporating C 9 and C10 of the rexoid 165 compound into an aromatic (or pseudo-aromatic) ring, and X 1 , X", R, R", Ring, Z, a and b are as defined above. 29. A composition according to claim 28 wherein Ring is a cyclohexyl ring having the following structur : wherein: each R is independently selected from H, halogen, alkyl, aryl, hydroxy, thiol, alkoxy, thioalkoxy, amino, or any of the Z substituents; 15 any one of C 2, C3, or C4 can be replaced with -0-, carbonyl (>C0) , -S-, -S(O)-, -S(0) 2 -, thiocarbonyl (>CS) , or -NR"-; R" is hydrogen, alkyl, hydroxy, thiol, or alkoxy acyl; and 20 said cyclic moiety exists as the saturated, 2-ene, 3-ene, 4-ene, or 5-ene mono-unsaturated isomer, or the 2,4-, 2,5-, or 3,5-diene derivative thereof; or an aromatic derivative thereof.

Inventors: BOEHM MARCUS F, EICHELE GREGOR, EVANS RONALD M, HEYMAN RICHARD A, MANGELSDORF DAVID J, THALLER CHRISTINA, BOEHM, MARCUS, F., EICHELE, GREGOR, EVANS, RONALD, M., HEYMAN, RICHARD, A., MANGELSDORF, DAVID, J., THALLER, CHRISTINA
Applicants: BAYLOR COLLEGE MEDICINE, LIGAND PHARM INC, SALK INST FOR BIOLOGICAL STUDI, BAYLOR COLLEGE OF MEDICINE, LIGAND PHARMACEUTICALS, INC., THE SALK INSTITUTE FOR BIOLOGICAL STUDIES
Application year: 1992
Main classification: C07C403
IPC codes: A61K31, A61K38, A61P3, A61P35, A61P43, C07C57, C07C59, C07C403, C07K14, C12P7, C12P9, G01N33