Multiple central alpha 2 adrenoceptors of avian and mammalian species.

Although equilibrium binding experiments indicated that calf cerebral membranes contained two classes of clonidine receptors and that chicken cerebral membranes might have contained only one, experiments investigating the kinetics of binding and the effects of GppNHp clearly indicated that the cerebral membranes of both species contained two subtypes of receptor, with the avian high affinity receptor having been present at too low a density to be readily detected in equilibrium binding studies. For both species 10 microM GppNHp sharply reduced or eliminated both the high affinity binding site and the slow steps of association and dissociation without changing the low affinity site and its related rapid association and dissociation steps. The high affinity sites from both species had similar specificities since the relative affinities of the avian binding site for a series of clonidine analogues closely reflected the relative affinities of the calf binding site. The properties of the chicken and calf alpha 2 subtypes resembled those reported for rat brain.

Preparation of some 10-[3-(dimethylamino)-1-propyl]-10H-pyrazino[2,3-b][1,4] benzothiazines as potential neuroleptics.

Chloro- and methyl-substituted 10H-pyrazino[2,3-b][1,4]benzothiazines were prepared and their structures determined by 13C NMR and X-ray crystallographic analysis. Alkylation afforded the 10-[3-(dimethylamino)-1-propyl] derivatives, which were compared to chlorpromazine in receptor-binding assays, in vivo behavioral tests, and electrochemical oxidation studies. In this series, the 2-chloro compound, 4c, proved to be the most effective derivative in displacing [3H]siperone, [3H]apomorphine, and [3H]prazosin radioligands from binding sites, being approximately as potent as chlorpromazine in this respect. However, none of the 10H-pyrazino[2,3-b][1,4]benzothiazines of this study were as active as chlorpromazine in in vivo tests predictive of neuroleptic activity.

Piperazinylimidazo[1,2-a]pyrazines with selective affinity for in vitro alpha-adrenergic receptor subtypes.

Regioselective syntheses of alkyl- and halogen-substituted piperazinylimidazo[1,2-a]pyrazines by novel oxidation-dehydration of [(beta-hydroxyalkyl)amino]pyrazines are described. Lanthanide shift reagent studies allowed correction of literature assignments of NMR chemical shifts and coupling constants for the imidazo[1,2-a]pyrazine ring system (e.g., J5,8 greater than J6,8). Equilibrium constants for displacement of specifically bound [3H]clonidine and [3H]prazosin from calf cerebral cortex homogenates in vitro are tabulated for reference and title compounds, and structure-affinity relationships for alpha 2- vs. alpha 1-adrenergic receptors are considered. Compound 2a, 8-(1-piperazinyl)imidazo[1,2-a]pyrazine, is equipotent with mianserin on the clonidine receptor (alpha 2) but ca. 70 times as selective as mianserin for this alpha 2-adrenergic receptor. Reduction of the imidazo ring (2,3-dihydro) lowers affinity for the alpha 2 receptor without affecting alpha 1-receptor affinity. Computer-assisted molecular modeling techniques are applied to the estimation of conformational energies of 2a and its 5-position isomer in relation to the semirigid molecule mianserin.

Quantitative structure-activity relationships involving the inhibition of glycolic acid oxidase by derivatives of glycolic and glyoxylic acids.

The enzyme glycolic acid oxidase oxidizes glycolate to glyoxylate and glyoxylate to oxalate. Three series of compounds related to the natural substrates, substituted glycolic, oxyacetic, and glyoxylic acids, have been investigated as inhibitors of this enzyme using the techniques of regression analysis and quantitative structure-activity relationships. The best overall correlation with inhibitory potencies was found with the Hansch hydrophobic parameter pi. The classical electronic parameters sigmap, sigmam, F, and R performed poorly. For the substituted glyoxylic acids, a dummy parameter relating to the presence of a nucleophilic group in close proximity to the alpha-carbonyl of the glyoxylate group was found to be highly significant. The syntheses of six novel glycolic and glyoxylic acids are described.