Beryl W. Dominy

X-ray analysis of a difluorostatone renin inhibitor bound as the tetrahedral hydrate to the aspartic protease endothiapepsin.

In this study we report the X-ray analysis of a complex between the aspartic protease endothiapepsin (EC 3.4.23.6) and an inhibitor bound as a carbonyl hydrate (gem-diol) to the catalytic aspartates of this enzyme, in a manner closely resembling the putative tetrahedral intermediate in proteolytic cleavage of the peptide bond.1 This study was undertaken in order to obtain a closer model of the interactions stabilizing this intermediate than those used in previous analyses, which were based on X-ray crystallographic data obtained from inhibitors lacking one or both of the hydroxyl residues of this species.2,3

Dopamine receptor blockade by imidoline and its proposed active conformation

Imidoline, 1-[2-(N,N-dimethylamino)ethyl]-3-m-chlorophenyl-2-imidazolidinone, has been found to be as potent as chlorpromazine in increasing striatal DOPA accumulation and prolactin secretion in vivo. In contrast, imidoline exhibited only weak inhibitory activity towards dopamine-sensitive adenylate cyclase and 3H-spiroperidol binding to striatal membranes in vitro. These neuroleptic effects in vivo are probably caused by blockade of dopamine receptors since imidoline did not deplete the striatum of dopamine. Imidoline is of interest because its structure is distinct from those of other neuroleptics. A proposed active conformation involves intramolecular hydrogen bonding between the protonated dimethylamino group and the oxygen of the imidazolidinone ring. The spatial relationship between the amine nitrogen and phenyl ring in this conformation allows proper fit of imidoline with key dimensions described for the dopamine receptor.