A vertical array of five hydrophones was used to measure the acoustic field in the vertical plane of singing humpback whales. Once a singer was located, two swimmers with snorkel gear were deployed to determine the orientation of the whale and position the boat so that the array could be deployed in front of the whale at a minimum standoff distance of at least 10 m. The spacing of the hydrophones was 7 m with the deepest hydrophone deployed at a depth of 35 m. An eight-channel TASCAM recorder with a bandwidth of 24 kHz was used to record the hydrophone signals. The location (distance and depth) of the singer was determined by computing the time of arrival differences between the hydrophone signals. The maximum source level varied between individual units in a song, with values between 151 and 173 dB re 1 microPa. One of the purposes of this study was to estimate potential sound exposure of nearby conspecifics. The acoustic field determined by considering the relative intensity of higher frequency harmonics in the signals indicated that the sounds are projected in the horizontal direction despite the singer being canted head downward anywhere from about 25 degrees to 90 degrees. High-frequency harmonics extended beyond 24 kHz, suggesting that humpback whales may have an upper frequency limit of hearing as high as 24 kHz.

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The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing offtarget pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.

Peptidic glucagon antagonists have been shown to lower blood glucose levels in diabetic models (1-3), but attempts to identify small molecular weight glucagon receptor-binding antagonists have met with little success. Skyrin, a fungal bisanthroquinone, exhibits functional glucagon antagonism by uncoupling the glucagon receptor from adenylate cyclase activation in rat liver membranes (1). We have examined the effects of skyrin on cells transfected with the human glucagon receptor and on isolated rat and human hepatocytes. The skyrin used was isolated from Talaromyces wortmanni American Type Culture Collection 10517. In rat hepatocytes, skyrin (30 µmol/l) inhibited glucagon-stimulated cAMP production (53%) and glucose output (IC 50 56 µmol/l). There was no detectable effect on epinephrine or glucagon-like peptide 1 (GLP-1) stimulation of these parameters, which demonstrates skyrin's selective activity. Skyrin was also evaluated in primary cultures of human hepatocytes. Unlike cell lines, which are largely unresponsive to glucagon, primary human hepatocytes exhibited glucagon-dependent cAMP production for 14 days in culture (EC 50 10 nmol/l). Skyrin (10 µmol/l) markedly reduced glucagon-stimulated cAMP production (55%) and glycogenolysis (27%) in human hepatocytes. The inhibition of glucagon stimulation was a specific property displayed by skyrin and oxyskyrin but not shared by other bisanthroquinones. Skyrin is the first small molecular weight nonpeptidic agent demonstrated to interfere with the coupling of glucagon to adenylate cyclase independent of binding to the glucagon receptor. The data presented in this study indicate that functional uncoupling of the human glucagon receptor from cAMP production results in metabolic effects that could reduce hepatocyte glucose production and hence alleviate diabetic hyperglycemia.