Although acetaminophen is a well established analgesic, its mechanism of action is still unknown. We investigated whether this drug could affect central monoaminergic neurotransmission in rats. Significant increases in serotonin (5-HT) levels were found in the posterior cortex, hypothalamus, striatum, hippocampus and brain stem, but not spinal cord, 45 min after per os administration of 200–400 mg/kg of acetaminophen. However, this treatment altered neither the levels of 5-hydroxyindoleacetic acid nor the accumulation of 5-hydroxytryptophan after blockade of aromatic L-amino acid decarboxylase. On the other hand, a decrease in both the levels of the dopamine (DA) metabolite, dihydroxyphenylacetic acid, and the accumulation of dihydroxyphenylalanine were noted in the striatum of acetaminophen-treated rats. Finally, acetaminophen administration significantly increased noradrenaline (NA) levels in the posterior cortex. In vitro studies showed that acetaminophen (1 mM) enhanced K+-evoked overflow of [3H]5-HT, but not [3H]DA and [3H]NA, previously taken up in brain slices, and exerted no direct effect on monoamine oxidase A, tyrosine hydroxylase and catechol-O-methyl-transferase activities. These results indicate that acetaminophen affects central monoaminergic neurotransmission, thereby suggesting that monoamines (especially 5-HT) might participate in its analgesic action.

Based on the evidence that the antinociceptive effects of acetaminophen could be mediated centrally, tissue distribution of the drug after systemic administration was determined in rat anterior and posterior cortex, striatum, hippocampus, hypothalamus, brain stem, ventral and dorsal spinal cord. In a first study, rats were treated with acetaminophen at 100, 200 or 400 mg/kg per os (p.o.), and drug levels were determined at 15, 45, 120, 240 min by high performance liquid chromatography (HPLC) coupled with electrochemical detection (ED). In a second study, 45 min after i.v. administration of [3H]-acetaminophen (43 μCi/rat; 0.65 μg/kg), radioactivity was counted in the same structures, plus the septum, the anterior raphe area and the cerebellum. Both methods showed a homogeneous distribution of acetaminophen in all structures studied. Using the HPLC-ED method, maximal distribution appeared at 45 min. Tissue concentrations of acetaminophen then decreased rapidly except at the dose of 400 mg/kg where levels were still high 240 min after administration, probably because of the saturation of clearance mechanisms. Tissue levels increased with the dose up to 200 mg/kg and then leveled off up to 400 mg/kg. Using the radioactive method, it was found that the tissue/blood ratio was remarkably constant throughout the CNS, ranking from 0.39 in the dorsal spinal cord to 0.46 in the cerebellum. These results, indicative of a massive impregnation of all brain regions, are consistent with a central antinociceptive action of acetaminophen.

A series of 1-benzylbenzimidazole and 3-benzylimidazo[4,5-b]pyridine substituted in the 2-position by an alkanoic or mercaptoalkanoic acid chain was synthesized for evaluation as potential thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists. The affinity of each compound for washed human platelet TXA2/PGH2 receptors was determined by radioligand binding studies using [125I]PTA-OH. Structure-activity relationships led to the conclusions that 2-alkanoic acid derivatives were slightly more potent than 2-mercaptoalkanoic acids and that compounds possessing a 3,3-dimethylbutanoic acid in the 2-position were definitely the most potent with Ki values of 4-39 nM (11a, 11g-x, 37a, 37f-o, 23a-c). The replacement of this 3,3-dimethylbutanoic acid side chain by a shorter one led to a marked decrease of affinity (11b and 11c; Ki = 5600 and 1700 nM, respectively). Compounds of benzimidazole and imidazo[4,5-b]pyridine series displayed similar potencies (11q and 23c have Ki values of 6 and 7 nM, respectively). The interesting pharmacological profile of compound 23a (UP 116-77: 4-[3-[(4-chlorophenyl)methyl]-6-chloroimidazo[4,5-b]pyridin-2-yl]- 3,3-dimethylbutanoic acid) and its excellent tolerance led us to select this derivative for further development.

The onset of diabetic complications may be prevented by the inhibition of aldose reductase. Derivatives of N-(quinolinyl thiocarbonyl) glycine were prepared and their in vitro and ex vivo aldose reductase inhibitory activities were tested on rat lens. The cincophen derivatives were the most potent in vitro with an enzyme inhibition value of 29% at 10−8 M and 91% at 10−7 M for the N-[(2-phenylquinolin-4-yl)thiocarbonyl]-N-methylglycine compound 10a. This activity was shown to be dependent on the nature of the substituents and seems to be optimal for the acids; esters were found to be inactive. No compound have shown ex vivo inhibitory activity. It is concluded that the lack of ex vivo activity is likely due to a poor bioavailability or a bad penetration of the compounds in target tissue (lens).

AbstractThe effects of UP 614‐04, a potential antidepressant agent, and those of some known antidepressant agents on cerebral monoamine oxidase (MAO) activity were compared in rats and mice. Using ex vivo and in vitro techniques, it was shown that UP 614‐04, a viloxazine analogue, inhibited cerebral MAO activity in rats and mice ex vivo, but that it was not effective in vitro. Time‐course studies revealed that the action of UP 614‐04 was more sustained than that of viloxazine, but much less potent or sustained than those of pargyline or isocarboxazide. The effect of UP 614‐04 was not selective to the A or B forms of MAO.