Miguel A. Toledo

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

Nociceptin/orphanin FQ (N/OFQ), a 17 amino acid peptide, is the endogenous ligand of the ORL1/nociceptin-opioid-peptide (NOP) receptor. N/OFQ appears to regulate a variety of physiologic functions including stimulating feeding behavior. Recently, a new class of thienospiro-piperidine-based NOP antagonists was described. One of these molecules, LY2940094 has been identified as a potent and selective NOP antagonist that exhibited activity in the central nervous system. Herein, we examined the effects of LY2940094 on feeding in a variety of behavioral models. Fasting-induced feeding was inhibited by LY2940094 in mice, an effect that was absent in NOP receptor knockout mice. Moreover, NOP receptor knockout mice exhibited a baseline phenotype of reduced fasting-induced feeding, relative to wild-type littermate controls. In lean rats, LY2940094 inhibited the overconsumption of a palatable high-energy diet, reducing caloric intake to control chow levels. In dietary-induced obese rats, LY2940094 inhibited feeding and body weight regain induced by a 30% daily caloric restriction. Last, in dietary-induced obese mice, LY2940094 decreased 24-hour intake of a high-energy diet made freely available. These are the first data demonstrating that a systemically administered NOP receptor antagonist can reduce feeding behavior and body weight in rodents. Moreover, the hypophagic effect of LY2940094 is NOP receptor dependent and not due to off-target or aversive effects. Thus, LY2940094 may be useful in treating disorders of appetitive behavior such as binge eating disorder, food choice, and overeating, which lead to obesity and its associated medical complications and morbidity.

Enantioselective Synthesis of (+)‐Royleanone from Sulfinyl Quinones

A convergent enantioselective synthesis of (+)-royleanone (1) is described starting from enantiomerically pure (S)-3-hydroxy-2-isopropyl-5-tert-butylsulfinyl-p-benzoquinone, which is readily available from 3-isopropyl-1,2,4-trimethoxybenzene and 1,3,3-trimethyl-2-vinylcyclohexene. The key step is a tandem asymmetric Diels-Alder reaction/pyrolytic sulfoxide elimination process.

Preclinical findings predicting efficacy and side‐effect profile of LY2940094, an antagonist of nociceptin receptors

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant‐ and anxiolytic‐related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2‐[4‐[(2‐chloro‐4,4‐difluoro‐spiro[5H‐thieno[2,3‐c]pyran‐7,4′‐piperidine]‐1′‐yl)methyl]‐3‐methyl‐pyrazol‐1‐yl]‐3‐pyridyl]methanol) displayed antidepressant‐like behavioral effects in the forced‐swim test in mice, an effect absent in NOP−/− mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential‐reinforcement of low rate schedule. Although anxiolytic‐like effects were not observed in some animal models (conditioned suppression, 4‐plate test, novelty‐suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear‐conditioned freezing in mice, stress‐induced increases in cerebellar cGMP in mice, and stress‐induced hyperthermia in rats. These are the first reports of anxiolytic‐like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5‐choice serial reaction time or delayed matching‐to‐position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant‐ and anxiolytic‐related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere.

Asymmetric Diels–Alder reactions of 5-substituted and 5,6-disubstituted (S)-2-(p-tolylsulfinyl)-1,4-benzoquinones with cyclopentadiene and trans-piperylene

Abstract A systematic study of reactions between 5-substituted and 5,6-disubstituted ( S )-2- p -tolylsulfinyl- p -benzoquinones and cyclopentadiene or trans- piperylene is reported. Complete regio and π-facial selectivities are observed. The different behaviours of cyclic and acyclic dienes in the presence of ZnBr 2 (cyclopentadiene showed reversed diastereoselection) and the role of BF 3 ·OEt 2 are discussed.

Regulation of Endogenous (Male) Rodent GLP-1 Secretion and Human Islet Insulin Secretion by Antagonism of Somatostatin Receptor 5

Incretin and insulin responses to nutrient loads are suppressed in persons with diabetes, resulting in decreased glycemic control. Agents including sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP4i) partially reverse these effects and provide therapeutic benefit; however, their modes of action limit efficacy. Because somatostatin (SST) has been shown to suppress insulin and glucagonlike peptide-1 (GLP-1) secretion through the Gi-coupled SST receptor 5 (SSTR5) isoform in vitro, antagonism of SSTR5 may improve glycemic control via intervention in both pathways. Here, we show that a potent and selective SSTR5 antagonist reverses the blunting effects of SST on insulin secretion from isolated human islets, and demonstrate that SSTR5 antagonism affords increased levels of systemic GLP-1 in vivo. Knocking out Sstr5 in mice provided a similar increase in systemic GLP-1 levels, which were not increased further by treatment with the antagonist. Treatment of mice with the SSTR5 antagonist in combination with a DPP4i resulted in increases in systemic GLP-1 levels that were more than additive and resulted in greater glycemic control compared with either agent alone. In isolated human islets, the SSTR5 antagonist completely reversed the inhibitory effect of exogenous SST-14 on insulin secretion. Taken together, these data suggest that SSTR5 antagonism should increase circulating GLP-1 levels and stimulate insulin secretion (directly and via GLP-1) in humans, improving glycemic control in patients with diabetes.