Bicyclic Hydantoins with a Bridgehead Nitrogen. Comparison of Anticonvulsant Activities with Binding to the Neuronal Voltage-Dependent Sodium Channel

Abstract

The anticonvulsant activity of diphenylhydantoin (DPH or phenytoin) is consistent with its actions on the neuronal voltage-dependent sodium channel. To further elucidate the binding requirements for this site, we synthesized several hydantoin analogs and evaluated these in in vitro sodium channel-binding and/or in vivo whole animal anticonvulsant assays. 5-Pentyl-5-phenylhydantoin (8), the most potent binder to the sodium channel in this study, had the same affinity as DPH (IC50 = 40 microM), revealing that one phenyl ring is sufficient for good interactions. Since our previous studies with monophenyl-substituted bicyclic 2,4-oxazolidinediones suggested that N3-alkylation and the conformational constraint of a 5-alkyl substituent over one face of the oxazolidinedione ring improved activity, we synthesized two examples of analogous bicyclic hydantoins. However, the bicyclic hydantoins were much less potent binders to the neuronal voltage-dependent sodium channel than their monocyclic counterparts. The binding activity for the more potent bicyclic hydantoin, 1,8-diaza-9,10-dioxo-7-phenylbicyclo[5.2.1]decane (4) (IC50 = 427 microM), was comparable to that of the ring-opened, N3-methylated monocyclic hydantoin model, 5-butyl-3-methyl-5-phenylhydantoin (9) (IC50 = 285 microM), and these were 8-11 times less potent than the monocyclic model 8, which contains a free imide NH. Furthermore, 5-butyl-5-phenylhydantoin (7; IC50 = 103 microM) was less potent than 8, suggesting that increased log P may enhance binding. Thus, unlike 2,4-oxazolidinediones, N3-alkylation of hydantoins dramatically decreases sodium channel-binding activity. Bicyclic hydantoin 4 was nevertheless a good anti-MES anticonvulsant in mice (ED50 = 86 mg/kg), although this activity likely results from mechanisms other than interactions at the neuronal voltage-dependent sodium channel. Compound 4 was also relatively neurotoxic (TD50 = 124 mg/kg). These results suggest that the binding of hydantoins to the sodium channel may be enhanced by (a) a free imide NH group and (b) an increased log P. Furthermore, 2,4-oxazolidinediones and hydantoins must either orient differently in the same binding site or interact with different sites on the neuronal voltage-dependent sodium channel.

An Investigation of the Efficacy of Mood Stabilizers in Rodent Models of Prepulse Inhibition

“…Phenytoin, like lamotrigine and carbamazepine, is a use-dependent sodium channel blocker (Brouillette et al, 1994) and, like lamotrigine, modulates glutamate transmission (Cunningham et al, 2000). Nevertheless, it did not reduce the disruptive effects of ketamine on PPI.…”

Unambiguous structural characterization of hydantoin reaction products using 2D HMBC NMR spectroscopy

“…Two of the products summarized in Table 1, 5(a-b), remained as 2 that were isolated in poor yields (14-17%). Numbering follows from the hydantoin (3) core to maintain atom type consistency within the three structural types (2)(3)(4). Figure 2.…”

“…Before initiating laboratory work of this magnitude, it is essential that the reaction product be identified correctly and unambiguously. In the synthetic reaction discussed here, where hydantoins form by the opening of pyroglutamate esters (1) with isocyanates or thioisocyanates, there is the potential to form three distinct types of compounds (2)(3)(4), as shown in Fig. 1.…”

“…1. Two of these structural cores, the hydantoins (3) and the perhydro-1,3-diazepine-2, 4-diones (4), are of interest to medicinal chemists. Hydantoins have been shown to be active against several biological targets, 3 -5 while 4 are potent deanimase inhibitors.…”

Fluorous parallel synthesis of a hydantoin/thiohydantoin library

“…Aplysinopsins are isolated from marine organisms, and they exhibit cytotoxicity to cancer cells and ability to affect neurotransmitters [35][36][37]. Other hydantoin derivatives also exhibit a broad range of biological activities in medicinal (antitumor, anticovulsant, antimuscarinic, antiulcer, and antiarrythmic) [38][39][40][41][42] and agrochemical (herbicidal and fungicidal) [43][44][45][46][47][48][49] applications. In addition to solution phase synthesis [50][51], solid-phase synthesis of hydantoin has also been reported in the literature [52][53][54][55][56].…”