No description available.

No description available.

Drugs acting at 5-HT receptors were evaluated on three animal models of anxiety. On the elevated X-maze test the majority of 5-HT1 agonists were found to be anxiogenic. However, ipsapirone was anxiolytic and buspirone and gepirone were inactive. The 5-HT2 agonist DOI and the 5-HT2 antagonist ritanserin were anxiolytic while ICI 169,369, a 5-HT2 antagonist was inactive. All 5-HT3 antagonists tested were inactive in this test, while the indirect serotomimetics zimeldine and fenfluramine were anxiogenic. Neither beta-adrenoceptor agonists nor antagonists had reproducible effects on anxiety in this model. Combined beta-1/beta-2 adrenoceptor antagonists reversed the anxiogenic effects of 8-OH-DPAT while selective beta-1 or beta-2 antagonists did not. On the social interaction model the 5-HT1 agonists 8-OH-DPAT, RU 24969 and 5-MeODMT were anxiogenic and ipsapirone was anxiolytic. The 5-HT2 agonist DOI and the beta-adrenoceptor- and 5-HT- antagonist pindolol were anxiolytic, while the 5-HT2 and 5-HT3 antagonists were inactive. In the marble burying test, the 5-HT upake inhibitors zimeldine, fluvoxamine, indalpine and citalopram, the 5-HT1B/5-HT1C agonists mCPP and TFMPP and the 5-HT2/5-HT1C agonist DOI reduced marble burying without affecting locomotor activity. 5-HT1A agonists and the 5-HT2 and 5-HT3 antagonists were without effect. Lesions of the dorsal raphe nucleus reversed the anxiogenic effects of 8-OH-DPAT in the X-maze model. The implication of these results for the understanding of the pharmacology of 5-HT in anxiety is discussed.

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No description available.

No description available.

The development of classical and lipophilic inhibitors of dihydrofolate reductase (DHFR) as antitumour agents is reviewed and the advantages and problems associated with each class are discussed. The antitumour activity, pharmacokinetics and metabolism of m-azido-pyrimethamine (MZP), a novel lipophilic inhibitor, are considered and compared with metoprine, the prototype lipophilic antifolate. Evidence for a folate-independent target for lipophilic DHFR inhibitors is presented. Synthetic studies centred on three principal objectives. Firstly a series of structural analogues of MZP were prepared encompassing alkoxy, chloro and alkylamino substituents and evaluated, as the ethanesulphonate salts, for activity against mammalian DHFR. Inhibitory constant (KI) determinations were conducted by a Zone B analysis, the corresponding 4'-azido isomer of MZP proving more potent than the parent compound. Secondly, to facilitate metabolism and stability studies on MZP, a range of possible reference compounds were synthesised and characterised. Finally, a series of diaminopyrimidine derivatives were synthesised embracing structural features incompatible with DHFR inhibitory activity, in order that such compounds may serve as biochemical probes for the unidentified folate-independent target for lipophilic diaminopyrimidines discussed previously. Inactivity against DHFR was achieved via introduction of an ionic or basic group into a normally hydrophobic region of the molecule and compounds were screened against a mammalian DHFR and thymidylate synthase to confirm the abolition of activity. Several derivatives surprisingly proved potent inhibitors of DHFR exhibiting KI values comparable to that of methotrexate. Analogues were screened for antitumour activity in vitro and in vivo against murine leukaemia cell lines in order to identify potential lead compounds. Several derivatives virtually inactive against DHFR exhibited a disparate cytotoxicity and further biochemical studies are warranted. The nobreak hitherto unreported debenzylation of 2,4-diamino-5-(N-alkyl-benzylaminophenyl) pyrimidines was discovered during the course of the synthetic studies, treatment of these compounds with nitrous acid affording the corresponding benzotriazoles.

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Particulate microelectrophoresis was used to study changes in the surface properties of strains of Pseudomonas aeruginosa and Staphylococcus aureus with respect to changes of growth temperature and growth media which could he related to antibiotic resistance. Gentamicin-sensitive and intrinsically resistant strains of P. aeruginosa exhibited characteristic, but differently shaped pH-mobility curves; the shape was correlated with surface lipid. The surface properties and MIC values of cells grown at 37°C were not significantly affected by growth at 25°C. Cells of some resistant strains grown at 43°C became gentamicin-sensitive, surface lipid was lost and the shape of the pH-mobility curve altered. Surface lipid was related to intrinsic gentamicin resistance; surface lipid variations were independent of the growth media. Repeated subculture of P. aeruginosa in the absence of the antibiotic affected the R-factor strains only; resistance was lost after repeated subculture at 37 and 43°C. Cells of strain PL11 also lost both R-factor and intrinsic resistance mechanisms. When cells were grown on agar containing large amounts of divalent cations the mobility values were lower and the MIC values greater. These changes are attributed to the presence of a metal ion induced resistance barrier, due to association of calcium at the cell surface and to increased polysaccharide production. This barrier prevented the initial accumulation of gentamicin at the cell surface. Intrinsic gentamicin resistance is not due to the inability of gentamicin to bind to the cell surface. The uptake of calcium or gentamicin at the cell surface appeared to be a complex growth effect. Changes in cellular calcium could not be correlated with changes in the antibiotic resistance or surface properties of Staph, aureus. There was no correlation between the surface and biological properties of animal strains of Staph, aureus or between divalent cation content and methicillin resistance of human strains.

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