Jean-Guy Bizot-Espiard

Melatonin suppresses hyperglycemia caused by intracerebroventricular injection of 2-deoxy-D-glucose in rats

To elucidate the role of melatonin (MT), we examined the effects of intracranial injection of MT and an MT-antagonist (S20928) on the hyperglycemic response to intracranial injection of 2-deoxy-D-glucose (2DG) in rats. The hyperglycemic and hyperglucagonemic responses caused by intracerebroventricular injection of 2DG were inhibited by intracerebroventricular co-injection of MT, but enhanced by co-injection of the MT-antagonist. Intraperitoneal injection of MT also inhibited the hyperglycemic response, though the inhibition seemed to be less than that after intracranial injection of MT. These results suggest that MT plays an endogenously suppressive role in the hyperglycemia caused by 2DG, possibly through a brain site.

Effect of intravenous administration of melatonin on the efferent activity of the adrenal nerve

The effect of intravenous administration of melatonin on the efferent activity of the adrenal nerve was investigated in the rat. Intravenous infusion of 1 or 2 ng melatonin resulted in a decrease, and 10 or 20 ng or larger amount of melatonin caused an increase in the efferent activity of the adrenal nerve. The least effective dose for the suppressive activity of melatonin was 100 pg and the response is dose-related. Administration of either 1 ng or 10 ng of melatonin did not change the plasma glucose concentration until 30 min after the administration. Hepatic vagotomy eliminates the inhibitory effect of melatonin. These results suggest that melatonin sensors in the hepato-portal region and melatonin receptors in the SCN play important roles in the regulation of sympathetic outflow to the adrenal medulla.

Substituted pyrido[3,2-b]oxazin-3(4H)-ones: synthesis and evaluation of antinociceptive activity.

A new series of N-substituted pyrido[3,2-b]oxazinones has been synthesized, pharmacologically evaluated, and compared with acetyl salicylic acid. The compound with the maximal combination of safety and analgesic efficacy was 4-¿3-[4-(4-fluorophenyl-1-piperazinyl)propyl]¿-2H-pyrido[3,2-b]-1, 4-oxazin-3(4H)-one (6c) with ED50 values of 12.5 mg/kg po (mouse: phenylquinone writhing test) and 27.8 mg/kg po (rat: acetic acid writhing test), respectively. Compound 6c proved to be more active than aspirin with a safety index of 5.1.

N-substituted aminohydroxypyridines as potential non-opioid analgesic agents

A series of new N-substituted aminohydroxypyridines have been synthesized, pharmacologically evaluated and compared with their N-substituted oxazolopyridone analogs. The compound with the maximal combination of safety and analgesic efficacy was 3-[2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl]amino-2-hydroxypyridine (compound 10a), with ED50 values 0.4 mg kg-1 po (mouse: phenylquinone writhing test) and 0.5 mg kg-1 po (rat: acetic acid writhing test). Compound 10a possesses a potent non-opioid antinociceptive activity with moderate anti-inflammatory properties.

6-Aminoalkyloxazolo[4,5-b]pyridin-2(3H)-ones: Synthesis and Evaluation of Antinoceptive Activity

Series of 6-aminoalkyloxazolo[4,5-b]pyridin-2(3H)-ones incorporating structural modifications both in the alkyl chain and basic amino moiety were tested for their analgesic efficacy and safety in mice and rats. Two of the synthesised compounds, 4a (3-methyl-6-[(4-phenyl-1-piperazinyl)methyl]oxazolo[4,5-b]pyridin-2(3H)-one) and 12a (3-methyl-6¿1-[2-(4-phenyl-1-piperazinyl)ethan-1-ol]¿oxazolo[4,5-b]pyridin- 2(3H)-one) were found to be more potent than aspirin with ED50 values of 26 (16.1-42.4) and 15.5 (11.4-21.2) mg/kg po (mouse, phenylquinone writhing test) respectively and 6 (3.1-9.8) and 5.5 (3.5-8.8) mg/kg po (rat, acetic acid writhing test). Compounds 4a and 12a proved to be potent nonopioid nonantiinflammatory analgesics but unfortunately have sedative properties at relatively low doses (respectively 64 and 16 mg/kg po, mice).