The effect of meptazinol in the spinal cord on carrageenan-induced hyperalgesia was investigated. The latency of paw withdrawal (PWL) to a thermal stimulus was used as an index of inflammatory hyperalgesia in awake rats. Intrathecal (i.t.) injection of 10 and 100mg meptazinol markedly increased the PWL of the carrageenan-injected paw (P, 0:01). The PWL of the non-injected paw was not detectably affected by the administration of meptazinol at the doses tested. I.t. injection of naloxone (5mg) or atropine (1mg) alone exhibited no effect on the PWLs of either the carrageenan-injected or non-injected paw. Pretreatment with naloxone, but not atropine, completely blocked the meptazinol-induced anti-hyperalgesia. These observations suggested that mu opioid receptor rather than muscarinic acetylcholine receptor may be involved in the anti-hyperalgesia of meptazinol in the spinal cord.

Based on the known coumarin-based prodrug system, a new meptazinol (Z)-3-[2-(propionyloxy) phenyl]-2-propenoic ester (3) was designed and synthesized as prodrug to minimize the first-pass effect of meptazinol (1) and improve the oral bioavailability. The prodrug (3) showed a 4-fold increase in oral bioavailability over the parent drug meptazinol in rats.

Using the latency of paw withdrawal (PWL) from a noxious thermal stimulus as a measure of hyperalgesia, the effects of i.p. injection of meptazinol and its isomers, 112824 and 112825, on carrageenan-induced thermal hyperalgesia were studied in awaked carrageenan-inflamed rats. Peripheral inflammation was induced by intraplantar (i.pl.) injection of carrageenan (2mg/100μl) into one hindpaw in rats. Carrageenan produced marked inflammation (edema and erythema) and thermal hyperalgesia in the injected paws, which peaked at 3 h after injection and showed little change in magnitude for another 3h. Injection of 0.1mg/kg meptazinol (i.p.) at 3h after carrageenan had no effect on the PWLs of either inflamed or non-inflamed hindpaw during the next 100 min (P>0.05, n=8). At the dosage of 1 and 10mg/kg, meptazinol produced marked anti-nociception and anti-hyperalgesia in non-inflamed and inflamed hindpaw, respectively (P<0.05, n=8～11). The prolonging effect of meptazinol on PWL in inflamed hindpaw was more potent than that in non-inflamed hindpaw. Pre-administration of 1.5mg/kg naloxone significantly antagonized meptazinol-induced anti-nociception and anti-hyperalgesia. Intraperitoneal injection of an isomer of meptazinol, 112825 (1.5mg/kg), but not 112824 (1mg/kg), markedly increased the PWL of the non-inflamed hindpaw. Nevertheles, both the isomers produced similar anti-hyperalgesic effect to that of meptazinol (P<0.05, n=8), which was completely reversed by naloxone (1.5mg/mg). The results suggest that meptazinol and its isomers have anti-nociceptive and anti-hyperalgesic properties with the former more potent. The effects are mainly mediated by mu opioid receptors. This study provides an important clue for extending clinical utilization of meptazinol and its isomers.

A new rearrangement byproduct, 3-methyl-1,2,3,4,4a,4b,9a,15,15a,15b-decahydro-(4,5); (4a,15)-dimethanotricyclo-(4,3,1,02,7) deca [8,9,1,10-a,b,c]pyrido [4,3-a]-acridin-6-en-9-ol-8-one, has been isolated from the acid-catalyzed O-demethylation of 7-o-aminophenyl-6,14-endo-thenotetrahydrothebaine. The mechanism of its formation involving a novel annulation of the 6,14-endo-ethenylene moiety with the A ring aromatic carbons is discussed

间苯二酚常压催化氢化得到1，3环己二酮，经缩台、Reformatsky反应、脱氢反应，得到4苯并呋喃乙酸乙酯，再水解酸化后，得到依那朵林合成中的关键中间体4苯并呋喃乙酸。