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Kenakin, T. 1995 ; Agonist-receptor efficacy. II. Agonist trafficking of receptor signals. Trends Pharmacol. Sci. 16, 232-238, for instance, budesonide. Discontinued. Verizon states that the underlying reasons for rationing NXX codes are eliminated once pooling is implemented because unused numbers will need to be donated to the pool and shared by the pooling participants. Further, Verizon states that any continuation of rationing should be extended only to those carriers not participating in the pooling trial. Sprint argues that rationing of NXX codes is incompatible with FCC directives because it precludes carriers needing numbers from obtaining them. AT&T Wireless also argues the rationing should be ended with commencement of the pooling trial because the Commission's initial goals for extending the rationing plan will be moot upon implementation of the pooling trial. While we recognize the difficulty of rationing for carriers, we do not believe that ending rationing upon the commencement of pooling in the 412 NPA would serve our goal of preserving the life of both the 412 NPA and the 878 NPA. In response to Verizon's argument that rationing loses its rationale upon implementation of pooling, we do not agree because not all carriers participate in pooling. Therefore, while pooling may force a certain number of carriers to share numbering resources, it does not force all carriers needing numbering to do so. Consequently, implementation of the pooling trial alone does not guarantee that numbers in the 412 NPA will not be prematurely assigned to carriers. Regarding Sprint's argument that rationing violates FCC directives, we note that the continuation of the current industry consensus rationing plan until February 2002 was done through the express delegation of authority we received in the FCC's Delegation Order.21 Having determined that rationing should continue in the 412 NPA even upon implementation of the 1K pooling trial, we now consider AT&T Wireless' proposal regarding how to modify the rationing in consideration of pooling. AT&T Wireless submits that we should adopt an ``equal chance'' procedure which would allow all carriers to receive needed numbering resources in jeopardy situations. Under this procedure, carriers not participating in the pooling trial would participate in the rationing according to the already established rules. Carriers participating in the pooling trial would similarly participate in the rationing under the established rules once the pooling administrator certifies that these carriers' need for numbering resources cannot be met through the pool. Finally, the pooling administrator would participate in the lottery when there is less than 6 months inventory in a rate center until the NPA is 6 months from exhaust. We find merit in AT&T Wireless' approach to this situation in the sense that it attempts to ensure all carriers having a need for numbering resources be afforded the opportunity to receive them even in a rationing situation. However, we do have some concerns with this proposal such as the requirement that pooling carriers certify a need for numbers whereas non-pooling carriers do not need to do so. Further, there is no oversight regarding the pooling carriers' actual need for numbers. As we understand the proposal, the pooling administrator certifies that the carriers' need cannot be met by the numbering resources of the pool. However, the pooling administrator does not and should not be in the position of certifying that the need for the numbers exists. Because of these concerns, we have decided to establish different guidelines. To that end, we are going to direct the NANPA to set aside 15 NXX codes in the 412 NPA for the use of the pooling administrator. These 15 NXX codes. 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And urea moieties were incorporated with a view to improving solubility properties of the molecules. We were also interested in the in vitro antiparasitic activities of these compounds in view of previous aforementioned literature reports on related compounds.46 The synthesis of the target molecules was simple and straightforward and is depicted in Scheme 1. The amine scaffolds 5 were synthesised by reacting 6, 9-dichloro-2methoxyacridine 4 with a large excess of diamines in phenol. The resulting products were converted to the respective sulfonamide and urea products by standard reaction with the respective acid chloride and isocyanate. All new compounds gave 1H NMR, FABMS and, in relevant cases, microanalysis data consistent with their structures. The enzyme assays were performed essentially as described before.11 Recombinant T. cruzi TryR 128 mU ; was assayed using a Beckman DU640 spectrophotometer in 40 mM HEPES, pH 7.5, 1 mM EDTA and 200 mM NADPH at 25 C followed by the addition of 100 mM Try[SH]2. Human glutathione reductase, purified from human erythrocytes 42.3 mU ; , was analysed in a similar manner and under identical conditions followed by addition of glutathione disulfide 100 mM ; . Enzyme mixtures were preincubated with NADPH 10 min at 25 C ; before the addition of varying concentrations of inhibitor added in DMSO 1% v v final concentration ; . As can be seen from the data in Table 1, compounds 2 and 3 were generally superior to quinacrine in inhibiting TryR. Sulfonamides 2 were generally superior to ureas 3. This may be due to a more hydrophobic naphthalene moiety in 2 compared to the benzyl moiety in 3. However, despite the superior inhibitory activities of the derivatives, selectivity against the equivalent human enzyme, glutathione reductase, was lost. The loss of a positive charge from the terminal tertiary amino group ; in moving from quinacrine to the new derivatives could, for example, brucanyl ventolin.
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