Abstract 5548: Novel small-molecule delta opioid receptor ligands modeled from naltrindole inhibit the proliferation of human U266 multiple myeloma cells.

Abstract

Abstract Multiple myeloma is an invasive plasma cell neoplasm that proliferates in the bone marrow, and is responsible for 10% of all hematological malignancies. Naltrindole, synthesized by Portoghese and colleagues (1988) is a synthetic alkaloid derived from naltrexone, and has the pharmacological profile of a selective delta opioid receptor antagonist. Naltrindole also acts as a potent immunosuppressant in the allogeneic mixed lymphocyte reaction and in inhibiting renal graft rejection, and Gaveriaux-Ruff and colleagues (2001) demonstrated that a non-opioid receptor target was involved in the immunosuppressant activity of naltrindole. In a recent report (Mundra et al., J. Pharmacol. Exp. Ther. 342: 273-287, 2012), naltrindole inhibited human multiple myeloma cell proliferation in vitro and in a murine xenograft model in vivo, by interaction with a non-opioid receptor target. In this study, it was discovered that four novel small-molecule delta opioid receptor ligands (DOPs) derived from naltrindole by rational design (see Peng et al., Bioorgan. & Med. Chem. 17: 6442-6450, 2009) competed for specific 3H-naltrindole binding to human U266 multiple myeloma cells. The apparent dissociation constant, KD, of naltrindole binding to intact multiple myeloma cells was 20 μM, and the Bmax was 1.8 nmol/mg protein. Whole cells were incubated with 10 nM 3H-naltrindole in the absence and presence of 500 μM unlabeled naltrindole (to define specific binding), and the ability of the DOP ligands to displace specific naltrindole binding was assayed at room temperature following a 30 min incubation of each DOP compound at 50 μM. DOP 108 inhibited specific naltrindole binding down to 22 ± 6 % of control (78% inhibition of binding); DOP 121 reduced binding to 36 ± 10 % control; DOP 126 inhibited binding to 12 ± 5 % control, and DOP 402 inhibited binding to 16 ± 7 % control. More detailed competition curves will be performed, but it appears that the affinity of the DOP ligands for the naltrindole binding site are similar or higher than naltrindole itself. When U266 multiple myeloma cells were incubated at 37°C for 72 h in the presence of naltrindole or the DOP ligands, each at 50 μM, the number of viable myeloma cells was inhibited to 42 ± 7, 49 ±11, 31 ± 8, 29 ± 8, and 28 ± 9 % of the number of control untreated cells by naltrindole, DOP 108, DOP 121, DOP 126, and DOP 402, respectively, demonstrating that the efficacy of the DOP compounds to inhibit multiple myeloma cell growth was similar or better than naltrindole. This study provides a rationale basis for further evaluation of the DOP compounds as anti-multiple myeloma therapeutic agents. Citation Format: Richard D. Howells, Jyoti Joshi Mundra, Alessandro Howells, Giovanni Howells, Youyi Peng, William Welsh. Novel small-molecule delta opioid receptor ligands modeled from naltrindole inhibit the proliferation of human U266 multiple myeloma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5548. doi:10.1158/1538-7445.AM2013-5548