A series of (3R*,4R*)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists with varying substituents on the nitrogen were evaluated for their effect on food consumption in obese Zucker rats. ...Opioid affinity (mu, kappa, and delta for selected compounds) and opioid antagonist activity (mu and kappa) were characterized and compared to effects on food consumption. No compounds with high selectivity for either mu or kappa receptors were discovered. However, compounds in the series had exceptional potency as opioid antagonists and in reducing food consumption in the obese Zucker rat. In contrast, a few compounds with high potency as opioid antagonists had much weaker potency for inhibiting food consumption. (3R,4R)-3,4-Dimethyl-1-(3S)-3- hydroxy-3-cyclohexyl-propyl-4-(3-hydroxyphenyl)piperidine (11,LY255582) emerged as having the best activity profile, both in reducing food consumption and as an opioid antagonist. Compound 11 is a highly potent mu, kappa-, and delta-opioid antagonist with possible clinical utility as an appetite suppressant for weight loss.
A series of racemic N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines were evaluated for opioid agonist and antagonist activity at mu and kappa receptors. Several highly potent mu and ...kappa antagonists were discovered; however, no compounds with high selectivity for either the mu or kappa receptor were identified. Importantly, no derivative was found to have significant opioid agonist activity. Two derivatives were resolved, and the activities of the enantiomers were investigated. Only a limited stereochemical effect on opioid receptor selectivities was observed. The structure-activity relationships described establish the existence of an important lipophilic binding site distal to the nitrogen for both mu and kappa receptors and confirm the pure opioid antagonist pharmacophore nature of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine structure.
Taking to the airwaves Smith, M H; Snoddy, John
Electric perspectives,
11/1995, Letnik:
20, Številka:
6
Magazine Article
Personal communications services (PCS) are a new generation of wireless technology using the broad bands of the radio spectrum that were once the exclusive domains of public utilities and emergency ...services. The technology is about to take off, but to make that leap it needs an increased number of transmitter base stations, a fiber optic system, digital switching stations, and a supporting network. Those are wide-ranging requirements difficult for one company to provide by itself. Duke Power's DukeNet, Carolina Power & Light's CaroNet, BellSouth, and a group of independent telecoms are zeroing in on PCSs.
Surgical repair of the Taussig-Bing deformity has been successful in 2 children weighing 7.7 and 11.1 kg, respectively. In the first case the right ventricular patch diverted left ventricular blood ...to the pulmonary artery, thus creating a physiologically complete transposition which was then corrected by an interatrial Mustard baffle. In the second case a right ventricular tunnel diverted left ventricular blood to the aorta, and right ventricular blood was directed to the distal pulmonary artery by means of an external conduit bypassing a subpulmonic stenosis.
These patients represent the seventh and eighth successful corrections of the Taussig-Bing anomaly. One case (Patient 2) is the youngest to undergo repair and the first to receive an external conduit for bypass of an associated subpulmonic stenosis.
Charcot arthropathy of the shoulder and elbow is a rare disease process initially described in the 1700s; however, it was not until the 19th century that physicians understood its association with ...other disease processes such as cervical spine pathology and diabetes. A primary complaint is painful or painless joint dysfunction, meaning the orthopedic surgeon is regularly the first physician to evaluate the patient. Frequently, the condition of these patients is misdiagnosed. Although the pathogenesis of the disease is controversial, the etiology is commonly due to syringomyelia. The key to successful management is a thorough history and examination along with a workup including specific laboratory testing and imaging to rule out other disease processes. Most neuropathic shoulders and elbows have historically been managed conservatively because of poor outcomes with operative interventions. Newer data have emerged hinting that early neurosurgical intervention can stabilize this degenerative process. If clinical and radiographic stabilization occurs, recent studies have outlined surgical indications that can provide surgeons with a guide as to patients in whom successful operative outcomes can be achieved in the face of failed conservative management.
Edward de Bono, a man who believes he is a more powerful visionary than Plato, is setting up a consultancy to assist businesses develop. Its methods will be more from the old school of ...trouble-shooting than the discipline of lateral thinking that Mr de Bono fathered. Mr de Bono will provide the methods and inspiration for creative thinking, Cap Gemini Ernst & Young will manage the initial research and implement the ideas, Saatchi & Saatchi will provide the communications ideas and Shine will deal with public relations.
The Chemistry, a London networking forum for entrepreneurs and venture capital investors, is bucking the trend surrounding technology start-ups by today making its first foray into Europe. "We ...believe Munich's thriving venture capital community is the perfect environment for The Chemistry and is at the right stage of its development for us to make the greatest difference," Mr Mark Simon insisted. The firm brings together what it claims are "top-notch" venture capitalists with vetted start-ups and "serial entrepreneurs" at its invitation-only events where, The Chemistry says, there is a one-to- one ratio of investor to entrepreneur.
Extensive investigation into the issue of sexual abuse in institutional settings in the Catholic Church in Australia and beyond has shocked the church into action. The sins of commission and omission ...by Catholic clerics in relation to the sexual abuse of children and vulnerable people is now common knowledge. In the Australian context the report of the five-year-long Royal Commission into Institutional Responses to Child Sexual Abuse began on 13 January 2013. On 15 December 2017 the Royal Commission presented its final report to the Australian Governor-General, detailing the culmination of that inquiry.
The mitochondrial permeability transition (MPT) mediates hepatic necrosis after ischemia and reperfusion (I/R). Here, we studied the role of c-Jun N-terminal kinase 2 (JNK2) in MPT-induced liver ...injury. Wildtype (WT) and JNK2 knockout (KO) mice underwent 70% liver ischemia for 1 hr followed by reperfusion for 8 hr, after which hepatocyte injury and animal survival was assessed. Compared with WT, JNK2 KO mice had 38% less alanine transaminase release and 39% less necrosis by histology. Survival out to 14 days was also greater in JNK2 KO mice (57% vs. 11%), and overall Kaplan-Meier survival was improved. No difference in apoptosis was observed. Intravital multiphoton microscopy of potential-indicating rhodamine 123 after reperfusion revealed depolarized mitochondria in 82% of WT hepatocytes, which decreased to 43% in JNK2 KO hepatocytes. In conclusion, JNK2 contributes to hepatocellular injury and death after I/R in association with increased mitochondrial dysfunction via the MPT.
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