Biomedical subjects
Publications and source records attributed to W Greenlee.
Novel, selective M2 muscarinic antagonists, which replace the metabolically labile styrenyl moiety of the prototypical M2 antagonist 1 with an ether linkage, were synthesized. A detailed SAR study in this class of compounds has yielded highly active compounds that showed M2 Ki values of < 1.0 nM and >100-fold selectivity against M1, M3, and M5 receptors.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.
Identification of a number of highly potent M2 receptor antagonists with >100-fold selectivity against the M1 and M3 receptor subtypes is described. In the rat microdialysis assay, this series of compounds showed pronounced enhancement of brain acetylcholine release after oral administration.
OBJECTIVE: To determine whether memory scores after second intracarotid amobarbital procedure (IAP) injections are affected by the time between the first and second injections. METHODS: Sixty-two patients received their second IAP injection on the day after the first injection. Forty-three other patients received the second injection on the same day as the first injection. Both groups underwent similar IAP protocols and memory assessments, except for the timing of the second injection. RESULTS: The second IAP memory scores in the two-day group were significantly higher (p < 0.05) than those in the one-day group. Timing of second injection was a significant correlate of second memory scores, but amobarbital dosage, first IAP memory score, and pre-IAP measures of memory and intelligence were not significant correlates. CONCLUSION: One-day and two-day IAP protocols do not result in similar memory scores after the second injection. Nineteen percent of a subset of patients in the one-day protocol were misclassified, in terms of IAP memory ratings, because of the deleterious effect of having both injections on the same day. It is recommended that correction scores be considered, for some patients who receive two IAP injections on one day, to approximate what the second IAP memory score would have been had the second injection occurred on a second day.
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L6 myoblasts were used as an in vitro model to investigate the role of moniliformin and its interaction with monensin in turkey knockdown syndrome and sudden death syndromes in poultry. Cell viability and microscopic and ultrastructural alterations noted in L6 myoblasts cultured in the presence of moniliformin (0.0-0.3 microgram/microliter) were compared to those observed in parallel cultures also containing one of the following compounds: selenium (0-0.004 ng/microliter), thiamine (0-0.3 microgram/microliter), or pyruvate (0-0.46 microgram/microliter). Marked dilation of the RER, membranous whorls, glycogen deposition, membrane-bound cytoplasmic inclusions and necrosis were observed in myoblasts exposed to 0.03-0.30 microgram moniliformin/microliter medium. Supplementation of medium with thiamine and pyruvate, or selenium, provided significant protection to cells exposed to 0.0-0.3 microgram/microliter or 0.0-0.15 microgram moniliformin/microliter, respectively. Dose-dependent differences in protein and ATP production were not detected. Myoblasts grown in medium containing 0-0.15 microgram moniliformin/microliter and 7.5-50.0 microM A23187, beauvericin or monensin had degrees of cytotoxicity similar to parallel cultures receiving only an ionophore. L6 myoblasts were a useful model of moniliformin toxicosis. The findings of this study suggest cytotoxicity due to moniliformin in L6 myoblasts may be due in part to oxidative damage and altered pyruvate metabolism, and that moniliformin does not predispose myoblasts to ionophore toxicosis. This study supports the results of in vivo investigations in poultry that moniliformin and monensin do not act synergistically to induce knockdown or monensin toxicosis.
RATIONALE AND OBJECTIVES: We evaluated the feasibility of using a metallic stented portal vein as a conduit for portacaval shunt in pigs. METHODS: A metallic self-expanding stent was placed in the portal vein of five pigs under combined ultrasound and fluoroscopic guidance via a percutaneous transhepatic approach. After 6 weeks, a portacaval shunt was performed using the stented portal vein as a conduit. A single angiogram followed immediately by sacrifice and histologic examination was performed on each pig at a varying time interval postshunt. RESULTS: One pig died 3 days after the shunt procedure because of a presumed surgical technical failure and a consequent thrombosed portal vein. Angiographic patency of the portacaval shunt was confirmed in the four remaining pigs. Postmortem histologic evaluation showed more complete endothelialization and subintimal organization in the more chronic stents. Thrombus occurred only in the stent of the pig that died. There was no significant luminal obstruction in the other four stents. CONCLUSION: Our results suggest that a stented portal vein can be used successfully as a conduit for portacaval shunt in pigs.
BACKGROUND: The family of G protein coupled receptors is the largest and perhaps most functionally diverse class of cell-surface receptors. Due to the difficulty of obtaining structural data on membrane proteins there is little information on which to base an understanding of ligand structure-activity relationships, the effects of receptor mutations and the mechanism(s) of signal transduction in this family. We therefore set out to develop a structural model for one such receptor, the human angiotensin II receptor. RESULTS: An alignment between the human angiotensin II (type 1; hAT1), human beta 2 adrenergic, human neurokinin-1, and human bradykinin receptors, all of which are G protein coupled receptors, was used to generate a three-dimensional model of the hAT1 receptor based on bacteriorhodopsin. We observed a region within the model that was congruent with the biogenic amine binding site of beta 2, and were thus able to dock a model of the hAT1 antagonist L-158,282 (MK-996) into the transmembrane region of the receptor model. The antagonist was oriented within the helical domain by recognising that the essential acid functionality of this antagonist interacts with Lys199. The structural model is consistent with much of the information on structure-activity relationships for both non-peptide and peptide ligands. CONCLUSIONS: Our model provides an explanation for the conversion of the antagonist L-158,282 (MK-996) to an agonist by the addition of an isobutyl group. It also suggests a model for domain motion during signal transduction. The approach of independently deriving three-dimensional receptor models and pharmacophore models of the ligands, then combining them, is a powerful technique which helps validate both models.