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3-(Cyclopropylmethyl)-9-hydroxy-7-oxo-2,3,4,4a alpha,5,6,7,7a alpha- octahydro-1H-benzofuro[3,2-e]isoquinoline (4b) containing the ACNO ring system of morphine and a 7-keto function on ring C has been synthesized and found to possess potent PQW (ED50 = 0.15 mg/kg sc) and anti-Straub tail (ED50 = 0.02 mg/kg sc) activity. As compared to its 7-deoxy analog 1b, introduction of the 7-keto group did not significantly affect binding to any of the three opioid receptors (mu, kappa, and delta), but caused a 34-fold reduction in sigma-binding, suggesting reduced propensity to induce psychotomimetic effects. The C/D cis isomer of 4b (4c) was much less potent at the three opioid receptors, while displaying a slight increase in sigma affinity. Both 7-hydroxy derivatives 4e and 4f were active in anti-Straub tail assay (ED50 < or = 0.8 mg/kg sc), but only the alpha-isomer 4e demonstrated analgesic activity (PQW ED50 = 0.37 mg/kg sc) in the dose range tested. In guinea pig ileum preparations, 4e was characterized as a selective full agonist at the kappa opioid receptor (IC50 = 2.8 nM); while its beta-isomer 4f was a partial agonist (78% at 1 microM), with antagonist activity observed at both mu- and kappa-opioid receptors.

(+-)-(5 beta,7 alpha,8 beta)-3,4-Dichloro-N-methyl-N-[3-methylene-2- oxo-8-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-7-yl]benzeneacetamide (14) and its (5 alpha,7 alpha,8 beta) diastereomer 15 have been synthesized from 1,4-cyclohexanedione monoethylene ketal (1) in 10 steps. Compound 14, which we have designated SMBU-1, was found to bind with moderate affinity (Ki = 109 nM) and good selectivity (mu/kappa = 29) to the kappa opioid receptor, while 15 was only 1/10 as potent as a kappa ligand. Preincubation of brain membranes with 14 resulted in wash-resistant inhibition of kappa-receptor binding (69 +/- 6% of control at 10(-6) M). The ketone precursor trans-N-methyl-N-[5-oxo-2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide (12) showed a higher kappa-affinity (Ki = 78 nM) and a much higher kappa-selectivity (mu/kappa = 166) than 14. Compound 10, the ethylene ketal precursor of 12, exhibited a similar receptor binding profile to 14, with increased kappa-selectivity (mu/kappa = 55), while ketal 11, being a regioisomer of 10 and an oxygen isostere of the kappa-selective analgesic spiradoline (U-62,066), demonstrated the highest kappa-affinity (Ki = 1.5 nM) and kappa-selectivity (mu/kappa = 468) observed in this series.

Background/objectives Adipose tissue macrophages (ATMs) exist in either the M1 or M2 form. The anti-inflammatory M2 ATMs accumulate in lean individuals, whereas the pro-inflammatory M1 ATMs accumulate in obese individuals. Bee venom phospholipase A2 (bvPLA2), a major component in honeybee (Apis mellifera) venom, exerts potent anti-inflammatory effects via interactions with regulatory T cells (Treg) and macrophages. This study investigated the effects of bvPLA2 on a high-fat diet (HFD)-induced obesity in mice. Subjects/methods For in vivo experiments, male C57BL/6, CD206-deficient, and Treg-depleted mice models were fed either a normal diet 41.86 kJ (ND, 10 kcal% fat) or high-fat diet 251.16 kJ (HFD, 60 kcal% fat). Each group was i.p. injected with PBS or bvPLA2 (0.5 mg/kg) every 3 days for 11 weeks. Body weight and food intake were measured weekly. Histological changes in the white adipose tissue (WAT), liver, and kidney as well as the immune phenotypes of the WAT were examined. Immune cells, cytokines, and lipid profiles were also evaluated. The direct effects of bvPLA2 on 3T3-L1 pre-adipocytes and bone marrow-derived macrophages were measured in vitro. Results bvPLA2 markedly decreased bodyweight in HFD-fed mice. bvPLA2 treatment also decreased lipid accumulation in the liver and reduced kidney inflammation in the mice. It was confirmed that bvPLA2 exerted immunomodulatory effects through the CD206 receptor. In addition, bvPLA2 decreased M1 ATM and alleviated the M1/M2 imbalance in vivo. However, bvPLA2 did not directly inhibit adipogenesis in the 3T3-L1 adipose cells in vitro. Conclusions bvPLA2 is a potential therapeutic strategy for the management of obesity by regulating adipose tissue macrophage homeostasis.

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