u-50488 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

1. The authors describe here the effects of intravenous administration of RP 60180, a novel kappa agonist, on conscious baboons of the species Papio papio, which spontaneously present photically induced epileptic responses. 2. Animals (n = 2) were chronically implanted with epidural recording electrodes and tested whilst seated in a primate chair. The electrocorticogram (ECoG) and electrocardiogram (ECG) were recorded during a control period of at least 30 minutes before the injection of RP 60180 (1 to 4.5 mg/kg i.v.) and immediately afterwards. 3. Qualitatively, up to the dose of 4.5 mg/kg i.v., RP 60180 did not modify ECoG background in term of paroxysmal activity in comparison with that observed during the control period. It did not cause any manifest focal or generalized seizure discharges, nor did it consistently enhance or reduce photically induced myoclonic responses. 4. From the dose of 1 mg/kg i.v., RP 60180 slowed ECG frequency. This effect, which lasted for about 30 minutes post-injection, was most often seen at the higher doses. 5. In another set of experiments, one baboon received the kappa agonist U-50488 (a benzacetamide derivative of spiradoline) at 1 and 3 mg/kg i.v. U-50488, at 3 and to a lesser degree at 1 mg/kg i.v., induced paroxysmal bursts of slow wave ECoG activity and a slowing of the ECG. These effects lasted about 1 hour post-drug administration. During this period, we observed spontaneous vocalization, as if the animal were complaining, as well as shaking.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amino Acid Sequence; Animals; Electrocardiography; Electrodes, Implanted; Electroencephalography; Epilepsy; Hallucinogens; Molecular Sequence Data; Papio; Phenothiazines; Photic Stimulation; Pyrrolidines; Receptors, Opioid, kappa

1. The effects of U-54494A and U-50488H on convulsions produced by sound have been studied in genetically epilepsy-prone DBA/2 mice and genetically epilepsy-prone rats. 2. Both compounds showed a dose-dependent anticonvulsant activity. U-54494A was less potent as an anticonvulsant than U-50488H in genetically epilepsy-prone rats and elicited a similar potency to that of U-50488H in DBA/2 mice when administered intracerebroventricularly or intraperitoneally. 3. Similar sedative and hypothermic effects were observed after the highest dose of U-54494A and U-50488H in DBA/2 mice. U-50488H seems to exhibit a greater sedative effect and to affect the rotarod test in rats much more than U-54494A. U-54494A elicited a better therapeutic index than U-50488H. 4. The anticonvulsant properties of both compounds are antagonized by high doses of naloxone and nor-binaltorphimine, a selective kappa-opioid antagonist. 5. The effects of U-50488H and U-54494A in DBA/2 mice were also antagonized by the glycine/NMDA receptor antagonist D-serine. 6. The present results suggest a possible interaction between kappa-opioid and the glycine/NMDA receptors during epileptic phenomena.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anticonvulsants; Epilepsy; Female; Male; Mice; Mice, Inbred DBA; Motor Activity; Naloxone; Naltrexone; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Opioid, kappa; Serine

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Digestive System; Enkephalin, Leucine; Enkephalin, Methionine; Epilepsy; Kainic Acid; Male; Mice; Naloxone; Nervous System; Pyrrolidines; Receptors, Opioid