Biomedical subjects

T M DeLorey

Publications and source records attributed to T M DeLorey.

21 records · Page 2Linked to original sources

PubMed1990

Sodium channel binding and anticonvulsant activities of hydantoins containing conformationally constrained 5-phenyl substituents.

As a preliminary investigation of the importance of the aromatic ring orientation in interactions of 5-phenylhydantoins with the anticonvulsant site on the neuronal voltage-sensitive sodium channel, two isomeric hydantoins containing conformationally constrained phenyl rings and their monocyclic analogues were synthesized. One, a spirohydantoin (2) derived from alpha-tetralone, contains the plane of the phenyl ring in an orientation approximately perpendicular to that for the hydantoin ring. The other, a tricyclic hydantoin (4) derived from tetrahydroisoquinoline, contains the plane of the phenyl ring in an orientation roughly coplanar with that for the hydantoin ring. These compounds were evaluated in sodium channel binding and whole animal (mice) anticonvulsant assays. In both assays, 4 was significantly more potent than 2, suggesting that the anticonvulsant receptor site on the voltage-sensitive sodium channel may require a specific aromatic ring orientation.

Animals↗

PubMed1989

Sodium channel binding and anticonvulsant activities for the enantiomers of a bicyclic 2,4-oxazolidinedione and monocyclic models.

Racemic 7-phenyl-9,10-dioxo-1-aza-8-oxabicyclo[5.2.1]decane (1), a bicyclic 2,4-oxazolidinedione that we previously reported was a possible sodium channel anticonvulsant, was resolved into its enantiomeric forms, the absolute configurations were determined, and the stereoisomers were evaluated for relative sodium channel binding and whole animal anticonvulsant activities. Similar studies were carried out with two monocyclic models, 5-ethyl-5-phenyl-2,4-oxazolidinedione (2) and 5-ethyl-3-methyl-5-phenyl-2,4-oxazolidinedione (3). None of these isomers exhibited stereoselective effects in the sodium channel assay, and only modest enantioselectivities were observed for 2 and 3 in the anticonvulsant assays. (R)-(-)-1 was, however, 4 times more toxic than (S)-(+)-1 in the rotorod test, and due to its larger protective index, (S)-(+)-1 exhibited greater therapeutic potential than either (R)-(-)-1 or racemic 1.

Animals↗

PubMed1988

Anticonvulsant activities of phenyl-substituted bicyclic 2,4-oxazolidinediones and monocyclic models. Comparison with binding to the neuronal voltage-dependent sodium channel.

8,9-Dioxo-6-phenyl-1-aza-7-oxabicyclo[4.2.1]nonane (1) and 9,10-dioxo-7-phenyl-1-aza-8-oxabicyclo[5.2.1]decane (2), examples of anti-Bredt bicyclic 2,4-oxazolidinediones, were investigated as anticonvulsants in mice. Compound 2 was the more potent (anti-MES ED50 = 66 mg/kg), and its in vivo anti-MES effect was consistent with its in vitro potency of binding to the voltage-sensitive sodium channel (IC50 = 160 microM for the inhibition of binding of [3H]BTX-B), suggesting that 2 may be a new class I anticonvulsant. Several partial structures of 2, either monocyclic lactams or monocyclic 2,4-oxazolidinediones, were also evaluated in these assays, but no correlation was observed between sodium channel binding and anti-MES effects. A significant finding was that monocyclic 5-alkyl-5-phenyl-2,4-oxazolidinediones provided relatively potent, nontoxic, broad-spectrum anticonvulsants.

Animals↗