Hydrolysis of organophosphorus nerve agent soman by the monoclonal antibodies elicited against an oxyphosphorane hapten.

The antibody-mediated hydrolysis of the nerve agent O-1,2,2-trimethylpropyl methylphosphonofluoridate (soman) 1 has now been established with two monoclonal antibodies raised against the cyclic pentacovalent methyloxyphosphorane hapten 10 that mimics the pentacoordinated trigonal bipyramidal transition-state of the reaction. The hydrolysis reaction was studied using molecular orbital methods at the MP2/6-31 + G*/(/)HF/6-31 + G* level of accuracy. According to the ab initio calculations, the reaction seems to proceed via three separate transition-states. The calculations are in good agreement with the experimental results. The 1,3-dioxabenzophosphole hapten 10 was synthesized, coupled to the carrier protein and the antibodies were obtained by the hybridoma technique. Two antibodies, DB-108P and DB-108Q were found to enhance the rate of soman hydrolysis and they were kinetically characterised.

A semiempirical study on inhibition of catechol O-methyltransferase by substituted catechols.

Catechol and endogenous catechol derivatives are readily methylated by catechol O-methyltransferase (COMT). In contrast, many catechol derivatives possessing electronegative substituents are potent COMT inhibitors. The X-ray structure of the active site of COMT suggests that the methylation involves a lysine as a general base. The lysine can activate one of the catecholic hydroxyl groups for a nucleophilic attack on the active methyl group of the coenzyme S-adenosyl-L-methionine (AdoMet). We studied the effect of dinitrosubstitution of the catecholic ring at the semiempirical PM3 level on the methylation reaction catalysed by COMT. The electronegative nitro groups make the ionized catechol hydroxyls less nucleophilic than the corresponding hydroxyl groups of the non-substituted catechol. As a consequence, dinitrocatechol is not methylated but is instead a potent COMT inhibitor. The implications of this mechanism to the design of COMT inhibitors are discussed.

(R)-11-hydroxy- and (R)-11-hydroxy-10-methylaporphine: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.

(R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.

Pentacoordinate oxyphosphorane intermediate always exists in aqueous solution.

Gas-phase ab initio calculations indicate that dianionic pentacoordinate oxyphosphoranes do not have a kinetically meaningful intermediate. The simplest oxyphosphorane PO5H3(2-) has the least tendency to have a pentacoordinate intermediate. However, it does have a pentacoordinate intermediate when it is solvated with six water molecules. These results support the hypothesis that the phosphoryl transfer reactions take place via pentacoordinate intermediate not only in acidic but also in basic media.