The (E)-8-benzylidene and (E)-8-(3,4-dichlorobenzylidene), 7-ketone derivatives, 5 and 6, of the synthetic opiate 2-methyl-5-(3-hydroxyphenyl)morphan [5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1], were synthesized from the 7-ketone derivatives 2 or 4 via the Claisen-Schmidt reaction. The corresponding enantiomers of 5 and 6 were obtained in > 99% optical purity from the optical isomers of 4, resolved with the O,O'-dibenzoyltartaric acids. The absolute configurations of the enantiomers of 4 were determined by conversion, via Clemmensen reduction, to the enantiomers of 1, the configurations of which are known. The determination of the regioisomer and configurational isomer of 5, with respect to the introduced benzylidene group, was determined from a single-crystal X-ray analysis. 1H NMR data was used to confirm that 6 possessed the same configuration as 5. Radioreceptor binding studies in rat and guinea pig brain preparations revealed that (-)-(1S,5S)-5 displayed an 11-fold decrease in affinity for the opioid mu receptor and an increase in affinity for sigma receptors of 81-fold (low nanomolar affinity) relative to the ketone precursor (+)-(1S,5S)-4. An analogous, albeit less dramatic, trend was seen with compound (-)-(1S,5S)-6. Compounds (-)-(1S,5S)-5 and (-)-(1S,5S)-6 are distinct from the typical sigma-opiates in that they have very low affinity for either PCP sites or muscarinic receptors. The high affinity and selectivity of these novel sigma receptor ligands suggests that they will be valuable for the elucidation of the functional roles of sigma receptors.

The oral rexinoid bexarotene (Targretin) is widely used for treatment of cutaneous T-cell lymphomas (CTCL). We recently reported the first case of adult T-cell leukemia/lymphoma (ATLL) that responded rapidly to combination therapy of bexarotene and interferon (IFN)-␣2b with complete clinical response. We demonstrated that bexarotene induced apoptosis of the patient's malignant peripheral blood T-cells in vitro. However, our patient developed skin and nodal relapse 180 days after starting treatment. We now demonstrate that his peripheral blood malignant T cells became resistant to bexarotene-induced apoptosis. We investigated potential mechanisms that may cause aberrations in the retinoid X receptor ( IntroductionBexarotene is a third-generation novel retinoid X receptor (RXR)-selective retinoid ("rexinoid") that is FDA-approved for the treatment of cutaneous T-cell lymphoma (CTCL). 1 When used as a single agent in advanced refractory CTCL, oral bexarotene has a total response rate of 45% to 71% 1,2 with a duration of response from 3 to 17 months. Similar to other vitamin A derivatives such as all-trans retinoic acid, bexarotene is known to induce apoptosis and affect cellular proliferation, differentiation, and cytokine production, although the precise molecular mechanisms remain unknown. [3][4][5][6] This multitude of effects is likely because the RXRs, a family of nuclear hormone receptors, not only participate in retinoid signaling pathways as coregulators of retinoic acid receptors (RARs), but also form heterodimers with at least 20 other nuclear receptors. 7 Recently we confirmed the apoptotic effects of bexarotene and showed a dose-dependent effect of bexarotene in vitro on malignant peripheral blood T cells from patients with Sézary syndrome, a leukemic variant of mycosis fungoides/CTCL. However, the malignant T cells of one-third of patients tested remained consistently resistant to bexarotene-induced apoptosis. 6 The mechanism behind clinical and in vitro bexarotene resistance has not previously been reported. We sought to investigate bexarotene's apoptotic effects and RXR expression levels in a case of human T-lymphotropic virus (HTLV)-1-associated adult T-cell leukemia/lymphoma (ATLL) that initially responded dramatically to bexarotene and interferon-(IFN)-␣2b, but became clinically resistant after 180 days. Case reportWe previously reported a case of a 48-year-old man who presented with several months of diffuse papular erythroderma (total body erythema), fatigue, and chills. 8 Skin biopsies revealed CD4 ϩ CTCL. He had bulky axillary and pelvic lymphadenopathy which was confirmed by computed tomographic scan. Furthermore, he had peripheral blood involvement with an elevated white blood cell count of 18 100/L (47% polys, 42.4% lymphocytes, 10.1% mononuclear, 0.5% eosinophils, 0.1% basophils, absolute lymphocytes at 7700/L), an elevated CD4:CD8 ratio of 7.4 (normal Ͻ 4: 1), aberrant peripheral blood CD4 ϩ CD7 Ϫ and CD4 ϩ CD26 Ϫ T cell populations at 60% and 62%, respectively (normal populations typica...

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