Absorption and disposition of 14C-labelled oxiracetam in rat, dog and man.

The absorption and disposition of the nootropic drug oxiracetam (4-hydroxy-2-oxo-pyrrolidine-1-yl acetamide) were studied in rats and dogs (10 mg/kg i.v. and 10, 50 and 3000 mg/kg p.o.) and two healthy male volunteers (800 mg p.o.) using a [14C]-labelled preparation. Peroral absorption of [14C]-oxiracetam was incomplete in rats (28-42%), high in dogs (81-90%) and intermediate in man (about 56%). The rate of absorption was high in all species. Elimination was biphasic and the concentration of total radioactivity in blood and plasma declined rapidly with an initial elimination half-life of 1-3 h in all species. The specific systemic exposure to [14C]-oxiracetam was lowest in the rat, intermediate in the dog and highest in man. In all species the systemically available radioactivity was nearly exclusively excreted in urine in the form of unmetabolized oxiracetam. Whole-body autoradiography and quantitative determination of the radioactivity in various organs following i.v. and p.o. administration of [14C]-oxiracetam to rats demonstrated extensive distribution of the compound with high levels in kidney, liver, lung and skin, and very low levels in the brain. The radioactivity was rapidly eliminated from the body and minimal accumulation was observed upon repeated administration of 10 mg/kg for 8 days. Levels in the brain were still low, but higher than following a single dose, indicating slow diffusion across the blood-brain barrier. In pregnant rats treated with [14C]-oxiracetam radioactivity passed reversibly and to a limited extent through the placenta into fetal tissue.

CGP-12177. A hydrophilic beta-adrenergic receptor radioligand reveals high affinity binding of agonists to intact cells.

A new, hydrophilic beta-adrenergic receptor radioligand, (+/-)-[3H]CGP-12177 (4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2-on hydrochloride), was synthesized and radiolabeled to 40 Ci/mmol. The nonspecific binding of this compound to turkey erythrocyte ghosts and C6 glioma cell membranes was less than 5% of the total binding at five times the appropriate KD. Binding assays of intact C6 glioma cells also showed low nonspecific binding, less than 20% of the total binding at five times the appropriate KD. The affinities of the antagonists (-)- and (+)-propranolol as well as of the agonist (-)-isoproterenol were examined by their potency to displace various radioligands from intact C6 glioma cell and membrane preparations. With membrane preparations, both [3H] CGP-12177 and [3H]dihydroalprenolol (DHA) were displaced stereospecifically by the antagonists (-)- and (+)-propranolol and the agonist (-)-isoproterenol. With whole cells, [3H]CGP-12177 and [3H]DHA behaved differently. [3H]DHA and [3H]carazolol could be stereospecifically displaced by antagonists but only partially displaced by agonists, while [3H]CGP-12177 could be completely displaced by both antagonists and agonists as in membranes. In contrast to [3H]CGP-12177, the lipophilic ligand [3H]DHA is actually taken up by cells. The inability of agonists to displace lipophilic radioligands from receptors on intact cells may not be due to a low affinity of agonists for receptors on cells, but to an agonist-induced change in the receptors which renders them inaccessible to hydrophilic agonists and antagonists. This change is likely to be their internalization into the cell.

Are only alpha 2-adrenergic receptors present in bovine retina?

The retina represents a part of the central nervous system (CNS) with a well studied, geometrically defined structure and a specialized function--the processing of light signals. Neurotransmitters such as glutamate, aspartate, glycine, gamma-aminobutyric acid (GABA), dopamine and acetylcholine are considered to be involved in the neuronal activity of the retina. Receptors for acetylcholine, GABA, dopamine and benzodiazepines have also been demonstrated. Thus, the retina can be considered as a model for the study of neuronal processing in general, in which the input, light signals, can be selected and regulated in a defined way. We report here that alpha-adrenergic receptors in the bovine retina have been characterized using radioreceptor assays. 3H-phentolamine (an alpha 1- and alpha 2-antagonist), 3H-clonidine (a preferential alpha 2-agonist) and 3H-WB 4101 [(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane, an alpha 1-antagonist] were used as radioligands, and WB 4101 and prazosin (alpha 1-antagonists), tolazine (an alpha 2-antagonist), yohimbine and its stereoisomers rauwolscine (preference for alpha 2-receptors) and corynanthine (preference for alpha 1-receptors), were used as inhibitors of radioaligand binding. Only alpha 2-adrenergic receptors were found.