Potent relative

Bafilomycin Ai and Concanamycin F. Bafilomycin Ai (173) and eoncanamycin A (174) are members of the hygrolide family of macrolide antibiotics and act as potent, relatively specific, membrane ATPase inhibitors. As is clear from the structures, there is a strong stereochemical homology between these compounds (Scheme 9-50). 

Nausea-producing agents (eg, DM) may have substantial effectiveness but they can be toxic. Highly potent relatives of apomorphine (a well-known emetic) are known but they have rather low safety margins. (For further discussion of CN, CS, and DM, see Chapter 12, Riot Control Agents.) Psychochemical Agents... 

It has long been known that, amongst organic solvents, acetic anhydride is particularly potent in nitration, and that reaction can be brought about under relatively mild conditions. For these reasons, and because aromatic compounds are easily soluble in mixtures of nitric acid and the solvent, these media have achieved considerable importance in quantitative studies of nitration. 

Carbamates such as Aldicarb undergo degradation under both aerobic and anaerobic conditions. Indeed the oxidation of the sulfur moiety to the sulfoxide and sulfone is part of the activation of the compound to its most potent form. Subsequent aerobic metaboHsm can completely mineralize the compound, although this process is usually relatively slow so that it is an effective iasecticide, acaricide and nematocide. Anaerobically these compounds are hydrolyzed, and then mineralized by methanogens (61). 

Note that the relative spatial arrangement of the phenyl, amine, and hydroxyl functionahties are identical for (R)-alprenolol and (5)-sotalol. In addition to P-blocking activities, some of these compounds also possess potent local anaesthetic activity (see Anesthetics). The membrane stabilizing activity, however, is not stereoselective and correlates directly with the partition coefficient (hydrophobicity) of the compound. 

Desflurane is less potent than the other fluorinated anesthetics having MAC values of 5.7 to 8.9% in animals (76,85), and 6% to 7.25% in surgical patients. The respiratory effects are similar to isoflurane. Heart rate is somewhat increased and blood pressure decreased with increasing concentrations. Cardiac output remains fairly stable. Desflurane does not sensitize the myocardium to epinephrine relative to isoflurane (86). EEG effects are similar to isoflurane and muscle relaxation is satisfactory (87). Desflurane is not metabolized to any significant extent (88,89) as levels of fluoride ion in the semm and urine are not increased even after prolonged exposure. Desflurane appears to offer advantages over sevoflurane and other inhaled anesthetics because of its limited solubiHty in blood and other tissues. It is the least metabolized of current agents. 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Computer-aided inhibitor design is a relatively new and powerful approach for the development of novel, potentially potent, nonsubstrate-analogue enzyme inhibitors. Computer-aided methods and biological screening can each lead to new classes of novel inhibitors. However, computer-aided design methods can focus the search for inhibitors, thereby circumventing much of the time-consuming synthetic and natural product purification procedures for those compounds they find unlikely to function as inhibitors. 

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