Mechanism of action of the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline on Mycoplasma gallisepticum.

Evidence was found that the inhibitory action of Cu(DMP)2NO3, the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline (DMP), on Mycoplasma gallisepticum is a consequence of the ultimate toxicity of copper, and not that of the ligand, DMP. From uptake studies with radiolabeled 67Cu and [14C]DMP, we concluded that significantly more copper than DMP is bound to the mycoplasmal cell. It appeared that dissociation of Cu(DMP)2+ occurred shortly after interaction with the cell membrane. Copper was transported across the cytoplasmic membrane. A strong dependence of copper uptake on the incubation medium was observed in the absence of DMP. The main function of the ligand DMP appeared to be as a vehicle for the transport of copper from nontoxic copper-medium complexes to membrane-buried cellular ligands.

Mode of action of the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline on Mycoplasma gallisepticum.

Various physiological important activities of Mycoplasma gallisepticum were inhibited by the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline [Cu(DMP)2NO3]. The energy-yielding metabolism was inhibited because the conversion of pyruvate into lactate was found to be blocked by Cu(DMP)2NO3, indicating a selective inhibition of lactate dehydrogenase. Also, the production rate of acetate and the rate of oxygen uptake by whole cells of M. gallisepticum appeared to be strongly decreased. Experiments with crude cell extracts showed an inhibition of reduced nicotinamide adenine dinucleotide (NADH) oxidase by Cu(DMP)2NO3 and an even stronger inhibition of NADH oxidase and lactate dehydrogenase by CuSO4. No preferential inhibition of adenosine 5'-triphosphatase and pyruvate kinase was found. Investigations on the influence of Cu(DMP)2NO3 on deoxyribonucleic acid, ribonucleic acid, and protein synthesis with growing cells of M. gallisepticum showed a selective inhibition of the incorporation of [14C]thymidine into deoxyribonucleic acid. Cu(DMP)2NO3 induced a decrease in the total amount of accessible sulfhydryl groups of whole cells of M. gallisepticum, indicating that the observed diverse toxicity of Cu(DMP)2NO3 may be associated with the interaction of copper ions with protein sulfhydryl groups.

Mode of action of copper complexes of some 2,2'-bipyridyl analogs on Paracoccus denitrificans.

Copper complexes of 2,2'-bipyridyl and related compounds and CuSO4 inhibited the growth of paracoccus denitrificans. The copper(I) complex of 2,9-dimethyl-1,10-phenanthroline [Cu(DMP)2NO3] showed the highest activity, whereas the copper(II) complex of 1,10-phenanthroline and CuSO4 inhibited the growth to a lesser extent. The uncomplexed ligands (1,10-phenanthroline and 2,9-dimethyl-1,10-phenanthroline) showed little activity, but in the presence of noninhibitory amounts of CuSO4 this activity increased markedly. Copper ions therefore proved to be essential for the growth-inhibitor effect. The extent of inhibition appeared to be strongly dependent on the initial cell density and on the growth medium. No selective inhibition of deoxyribonucleic acid, ribonucleic acid, or protein synthesis was observed with Cu(DMP)2NO3. Respiratory electron transport of P. denitrificans appeared to be strongly inhibited by Cu(DMP)2NO3 and to a somewhat lesser extent by CuSO4. Both aerobic and anaerobic respirations were inhibited to the same extent, and from the cytochrome redox kinetics it is concluded that the site of this inhibition in the respiratory electron transport chain must be located before cytochrome b. Cu(DMP)2NO3 did not significantly influence the H+/O ratio with whole cells of P. denitrificans, suggesting that the efficiency of oxidative phosphorylation is not affected by CU(DMP)2NO3. Growing cultures of P. denitrificans showed a decrease in intracellular potassium ion content in the presence of increasing amounts of Cu(DMP)2NO3. It is concluded that interference with the cytoplasmic membrane, resulting in inhibition of respiratory electron transport, probably constitutes the main mode of action of copper complexes of 2,2'-bipyridyl analogs on P. denitrificans.

Pharmacokinetics of 2-phenyl-1,3-indandione in the rat after i.v. and oral administration.

The pharmacokinetics of the anticoagulant drug, 2-phenyl-1,3-indandione, after i.v and oral administration in the rat might be best described as a non-linear open two-compartment model with elimination fromthe peripheral compartment. The volume of the central compartment comprises the extracellular fluid.

Beta-adrenoceptor studies. 2. Effects of alkyl substitution on beta-adrenoceptor blocking, antiarrhythmic, and local anesthetic activities of 1,1'-(o-phenylenedioxy)bis(3-isopropylamino-2-propanol).

A series of bis(2-hydroxy-3-isopropylaminopropyl) ethers of nuclear-substituted catechols (1-7) has been synthesized and examined in vitro for beta-adrenoceptor blocking activity, antagonism of ouabain-induced arrhythmias, and local anesthetic activity. Both tracheal and right atrial beta-adrenoceptor blocking activity are markedly decreased by alkyl substitution in position 3 of parent catechol diether 1. Substitution in position 4 still lowers the affinity to cardiac arrhythmias and local anesthetic activity increases with introduction of alkyl substituents in the 3 as well as in the 4 position. In contrast with biological activities, the partition coefficient 1-octanol-phosphate buffer, pH 7.40, of 1 did not change significantly by 3- and 4-methyl substitution. Stepwise multiple regression analyses were performed using log P or pi values in combination with pKa(m), E8, or sigma. With cardiac beta-adrenoceptor blocking activity the optimal equation contained E8 and pi parameters, tracheal activity appeared to depend mainly on the E8 parameter, whereas for antiarrhythmic and local anesthetic activities the lipophilicity of the substituents appeared to be the determinant factor.