No abstract

1. The consequences of metabolic transformation on lipophilicity have been considered using the terms log P (partition coefficient) and log D (distribution coefficient). 2. Transformations which result in no change in the degree of ionisation can be readily predicted by the use of fragmental constants and log P. 3. If metabolism alters the degree of ionization then the distribution coefficient, log D, at physiological pH is a more appropriate term to use. Intuitive empirical observations may be incorrect and lead to false assumptions about the lipophilicity or water solubility of metabolites. 4. Metabolism may form zwitterionic molecules. These metabolites need special consideration since their penetration into lipid phases may be greater than expected.

No abstract

1. Metabolism of basic drugs may result in the formation of zwitterionic sulphate conjugates. The additional ionization introduced by the sulphate group into these compounds compared with the basic parent drug does not produce a corresponding increase in hydrophilic character. 2. Zwitterionic conjugates have constant lipophilicity between their pKa values. The opposite charges on the ionizing functional groups in this pH range appear to cancel the effect of each other on lipophilicity. 3. In the case of propranolol the O-sulphate derivative is more lipophilic than the parent compound at pH values below 7, despite the ionized character of the sulphate function. 4. The decrease in lipophilicity appears to be related to the separation in the molecular structure of the amino and sulphate groups.

No abstract

A combined molecular orbital/molecular mechanical computational model has been developed to study the potential energy surface of catalysis by the enzyme phospholipase A, . By the integration of molecular mechanical and quantum mechanical forces, the model allows the geometry optimisation of a molecule within a large and complex environment, such as the enzyme active site. The method has been applied to an examination of the role of histidine in the hydrolysis of an ester by phospholipase A, . Proton transfer to and from the imidazole ring of histidine is shown to be a valid mechanism, in that it occurs with minimal structural change and against a favourable potential energy surface.

No abstract

Abstract.Disodium 9-ethyl-4,6-dioxo-10-propyl-4H, 6H-pyrano[ 3,2-g] .12cm -l, F(000)=3904, T=291K, final R= 0-069 for 7317 unique observed reflections. The four tricyclic units are, within experimental error, identical, with side-chain groups on N(9) and C(10) extended away from the ring system. The carboxylate group on C(2) lies almost in the same plane as the pyranoquinoline ring, whereas the group on C(8) is almost perpendicular to this ring system. Within the crystal lattice the four tricyclic rings are pseudosymmetrically related and are s~acked one on top of each other up the b axis. Sodium ionsand water molecules lie in discrete channels and do not encroach into the tricyclic ring domain.