Showing papers by "Pierre Renard published in 1995"

Design and Synthesis of New Naphthalenic Derivatives as Ligands for 2-[125I]Iodomelatonin Binding Sites

Abstract: New melatonin-like agents were designed from the frameworks of 2,5-dimethoxyphenethylamine, an important structural moiety for the 5-HT receptor, and (2-methoxynaphthyl)-ethylamine. The compounds were synthesized by classical methods and evaluated in binding assays with chicken brain membranes using 2-[125I]iodomelatonin as the radioligand. Preliminary studies on the series of N-acyl-disubstituted phenethylamines showed the favorable role of the methoxy group in the ortho position of the side chain on the affinity for the receptor (Ki = 8 +/- 0.2 nM) for N-[2-(2-methoxy-5-bromophenyl)ethyl]propionamide (3o). This effect was confirmed in a series of the naphthalene derivatives, a bioisosteric moiety of the indole ring, and several potent ligands for melatonin binding sites were prepared such as N-[2-(2-methoxynaphthyl)ethyl]propionamide (4b) (Ki = 0.67 +/- 0.05 nM) and N-[2-(2,7-dimethoxynaphthyl)ethyl]cyclopropylformamide (Ki = 0.05 +/- 0.004 nM) (4k). Structure-activity relationships are discussed with regard to melatonin and bioisosteric naphthalenic compound 2. The Ki value for 4b was affected to a similar extent to that of melatonin by GTP-gamma-S or Mn2+ in competition experiments, suggesting an agonist profile for this compound.

N-substituted oxazolo[5,4-b]pyridin-2(1H)-ones: a new class of non-opiate antinociceptive agents.

Abstract: A series of 1-(aminoalkyl)- and 1-[(4-aryl-1-piperazinyl)alkyl]oxazolo[5,4-b]pyridin-2(1H)-one derivatives of oxazolo[5,4-b]pyridin-2(1H)-one, incorporating modifications to the length of the alkyl side chain and to the amino or 4-aryl-1-piperazinyl substituents, were tested for safety and analgesic efficacy in mice and rats. Some compounds with 4-(substituted or nonsubstituted phenyl)-1-piperazinyl substituents and a 3-4-carbon alkyl side chain had significantly greater analgesic activity than that of the oxazolo[4,5-b]pyridin-2(3H)-one analogs. To reduce the metabolic N-dealkylation of the piperazine observed in our previous work on oxazolo[4,5-b]-pyridin-2(3H)-ones, analogs of the most active compounds with steric hindrance on the alkyl side chain were prepared and tested. The compound with the maximal combination of safety and analgesic efficacy was 1-[[4-(4-fluorophenyl)-1-piperazinyl]propyl]oxazolo[5,4-b]pyridin- 2(1H)-one (compound 3b), with ED50 values of 5.6 mg/kg po (mouse, phenylquinone writhing test) and 0.5 mg/kg po (rat, acetic acid writhing test). Compound 3b is a potent, rapid-acting, non-opioid, nonantiinflammatory analgesic with low acute toxicity and sustained effect.

Regioselective Synthesis of Benzimidazolic Bioisosteres of Melatonin.

Abstract: A convenient synthesis of benzimidazolic bioisosteres of melatonin is described through a regioselective synthesis of 1,6-disubstituted benzimidazoles.