adenosine-5--(n-ethylcarboxamide) and Epilepsy

A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.

Topics: Amino Alcohols; Animals; Anticonvulsants; Chemistry, Physical; Dose-Response Relationship, Drug; Drug Design; Epilepsy; Male; Mice; Microsomes, Liver; Molecular Structure; Pilocarpine

The role of adenosine receptor agonists in the convulsant activity of mitochondrial toxin, 3-nitropropionic acid (3-NPA), was studied in mice. The occurrence of seizures evoked by peripheral application of 3-NPA was inhibited with the use of A1 adenosine receptor agonist, R-N6-phenylisopropyladenosine and A1/A2 agonist, 2-chloroadenosine. Moreover, both drugs prevented 3-NPA-induced mortality. Similarly, A1/A2 agonist, 5'-N-ethylcarboxamidoadenosine, protected against seizures evoked by the intracerebral administration of 3-NPA, and this effect was reversed by the co-application of adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline. Obtained results suggest that A1 adenosine receptor activation may modulate the chain of events leading to the development of 3-NPA-induced seizures.

Topics: 2-Chloroadenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Convulsants; Epilepsy; Hormone Antagonists; Male; Mice; Mitochondria; Neuroprotective Agents; Nitro Compounds; Phenylisopropyladenosine; Propionates; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Theophylline