A limited series of compounds structurally related to phenytoin has been tested in the maximal electroshock seizure (MES) test in order to define the impact on their antiepileptic activity of reducing the ability to form a hydrogen bond. A net stepwise decrease of the anticonvulsant activity was observed when the hydantoin ring structure was altered into succinimide and pyrrolidinone and when these rings were N-methylated. The pharmacological data analyzed in terms of structure-activity relationships (SAR) indicate the importance of the capability of forming hydrogen bonds. Further insight into the molecular mode of action of phenytoin was gained by a 13C NMR study of three phenytoin analogues deuterated in one of the phenyl groups, i.e., o-, m-, p-deuteriophenytoin. This approach allowed the unambiguous assignment of the chemical shifts of the ortho, meta, para, and ipso carbons. Measurement of the T1 relaxation times provided a value of 0.2 s for the para carbon and 0.8 s for the meta and ortho carbons of the phenytoin phenyl rings. These data are consistent with the view that the two phenyl groups possess a certain degree of rotational freedom along the para-ipso axis. More generally, the present results, as well as some literature data, support the concept that the ability to form hydrogen bonds as well as a certain degree of motional freedom of the phenyl groups are important SAR features in antiepileptic phenytoin-like drugs.

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A glyceride derivative of L-Dopa, 1,3-dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)propan oyl] propane-1,2,3-triol (1), was synthesized and tested as an orally administrable prodrug endowed with lymphotropic properties. In the oxotremorine and reserpine tests, 1 exhibited an anti-Parkinsonian activity of longer duration than L-Dopa. The time course of concentration of 1 in the intestinal lymph of rat was determined and compared to that of L-Dopa. The results clearly demonstrate that 1 is selectively absorbed from the intestinal tract by the lymphatic route without any chemical or enzymatic degradation. In the blood of rats and mice, 1 functions as a prodrug to release L-Dopa by hydrolysis. In comparison with L-Dopa itself, higher L-Dopa levels for a longer period of time were observed as well as much more favorable L-Dopa/dopamine ratios. Ultimately, studies using mice show that the administration of 1 brings about a prolonged increase of L-Dopa and dopamine levels in the brain, without initial transient peak in concentration observed after an equimolecular dose of L-Dopa.

ABSTRAGT Studies have been carried out on movements of Ca and Sr ions in rat small intestine, using the in vivo preparation developed by Curran and Solomon (5). In the concentration range of 0 to 25 raM, Sr flux appears to be passive, though restricted. Ca transport may not, however, be ascribed to passive independent movement of these ions since at higher concentrations (12.5 and 25 raM) Ca return from blood to intestinal lumen increases more than expected. An apparent diffusion coefficient of Ca and Sr ions in the membrane has been calculated and the influence of negative charges within the membrane on cation diffusion has been examined in a semiquantitative manner.Both Ca and Sr ions exercise a drastic effect on active Na absorption from intestine and on concomitant passive water movement. From 0 to 1 mM, Ca and Sr ions cause a sharp increase in Na and water efflux from the lumen. This rising phase is interpreted in terms of combination of the divalent cation with the Na carrier system following Michaelis-Menten kinetics. At concentrations higher than 1 mM, the effect of Ca and Sr ions is reversed and Na and water absorption decreases slowly as Ca or Sr concentration is increased. This failing phase is ascribed to a non-specific Ca effect which produces a general "stiffening" of the membrane.T h e present study is c o n c e r n e d with cation t r a n s p o r t across the small intestinal m u c o s a in the rat---specifically with C a a n d Sr fluxes a n d the effect exercised b y these ions on N a flux. T h o u g h the intestinal a b s o r p t i o n of C a has long b e e n studied (1-4), no specific m e c h a n i s m s of a b s o r p t i o n h a v e yet been d e m o n s t r a t e d . T h e e x p e r i m e n t s comprise an in vivo study of the a b s o r p -