对具有很高kappa受体亲和性和选择性的依那朵林进行了合成研究。以1，4环己二酮为原料，经缩合、环合、还原、环氧化等16步反应得到关键中间体1-[8-甲氨基-1-氧杂螺[4，5]癸烷-7-基]吡咯烷（16），再和4苯并呋喃乙酸在偶合剂CDI催化下得到目标化合物依那朵林。

目的 建立测定二对甲苯甲酞酒石酸美普他酚对映体的毛细管区带电泳法，并检测其光学纯度。方法 采用 72cmx 50pm未涂层石英毛细管，30mmol几磷酸缓冲液（州8.05，内含0.5% T M-βCD，乙睛12%），运行电压20kV，毛细管柱温20r，压力进样3kPax3s，检测波长200nm。结果在选定的实验条件下二对甲苯甲酞酒石酸美普他酚对映体达到基线分离。两对映体在0.10--0.80mg/mL的浓度范围内，浓度与峰面积的响应均呈良好的线性关系，相关系数分别为:0.9996和0.9998。迁移时间的RSD在3%以内，峰面积的RSD在10%以内，左旋体的加样回收率为100.26%（n=6），最低检测浓度为0.02mg/mLo测定3批样品的光学纯度分别为84.10%,92.54%,）99.60%。结论本法适用于实验室中二对甲苯甲酞酒石酸美普他酚光学纯度的常规测定。

Three meptazinol benzoyl esters (1-3) were synthesized as prodrugs to minimize the first-pass effect of meptazinol and improve the bioavailability. Among these three esters, compound 3 showed better bioavailability than the parent meptazinol. Further, the relative regional bioavailability of prodrug 3 was evaluated using in situ closed loop study in rats, which showed that prodrug 3 has higher absorption efficacy in rat intestine. Thusly, prodrug 3 may be worth for further development.

A nonlinear QSAR study was conducted on a series of 4-phenylpiperidine derivatives (4PPs) acting as μ opioid agonists by three-layer backpropagation neural network (NN) method. At first a variety of molecular descriptors were calculated and then selected with two-stage least squares combining partial least squares (PLS) method. The selected four molecular descriptors, out of 292 ones, were correlated with the known analgesic activities of 38 4PPs by NN method. The established QSAR model was further validated by five additional 4PPs, as an external testing set. Moreover, a pharmacophore model was hypothesized based on the results, which would be helpful for structural optimization of 4PPs.

Molecular modeling and 3D-QSAR studies were performed on 31 indolomorphinan derivatives to evaluate their antagonistic behaviors on jopioid receptor and provide information for further modification of this kind of compounds. Best predictions were obtained with CoMFA standard model (q2=0.693, N=4, r2=0.900) and CoMSIA combined model (q2=0.617, N=4, r2=0.904). Both models were further validated by an external test set of eight compounds with satisfactory predictions: r2=0.607 for CoMFA and r2=0.701 for CoMSIA. In addition, the 3D structure of human j opioid receptor was constructed based on the crystal structure of bovine rhodopsin, and the CoMSIA contour plots were then mapped into the structural model of j opioid receptor-GNTI complex to identify key residues, which might account for jantagonist potency and selectivity. The roles of nonconserved Glu297 and conserved Lys227 of human jopioid receptor were then discussed.

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。