Synthesis, Structure-Activity Relationship And Biological Study Of Novel Analgesics

Pain is a complex problem with staggering negative health and economic consequences. Non-opioid analgesics are illustrative of the most active fields of research and hopefully represent some of the more promising strategies for discovering more effective and safer pain medications to meet the challenges of the future. For discoverying new analgesic candidates with exclusively intellectual property, in this thesis a series of arylpiperazines with analgesic activity were successfully designed, synthesized and screened on animal models, then the structure-potency relationships were investigated; Furthermore, the toxicity, dose-effect relationship, and addiction as well as pharmacokinetics of the candidates were also studied intensitively.1. Several series of novel arylpiprazines were specifically designed and synthesized. The synthetic processes were fully investigated and optimized technical conditions have also been developed.Sixty-two new compounds were synthesized, and fifty-one of them were reported for the first time and the other nine ones only have CAS number without any detailed description. The structures of these compounds were characterized by NMR and MS.2. The compounds were screened with the in vivo anti-pain agents screening models including hot-plate test and acetic acid-induced abdominal writhing test and found twenty compounds displaying remarkable analgesic activity. The structure-activity relationship (SAR) was demonstrated according to the results obtained: (1) phenyl piperazine acetylbenzene derivative compounds presented dramatic pain-relieving potency,i.e. the potency increased while an electron-donating group was introduced into aromatic ring,In contrast,the potency decreased while an electron-withdrawing group was grafted into aromatic ring. (2) The potency of these compounds declined when phenyl was replaced with other heteroaryl groups; (3) The potency was retained if a carbon atom was added between phenyl and piperazine, but sedative activity was enhanced; (4) The potency significantly lowered if carbonyl was oximated; (5) The potency also reduced if 2, 5 positions of piperazine were substituted by methyl group. 3. Seven compounds displaying remarkable analgesic potency were selected for the acute toxicity evaluation. The LD50 values of three of them exceeded 2000mg/kg, and no side-effects were observed, so they were considered extremely safe. The LD50 determination of the other three ones were more than 477mg/kg and also can be viewed as safe agent compared with its pharmacodynamics dose (10, 20, 40mg/kg).4.Based on the above screening and evaluating system, six compounds with lower side-effect and potent antinociceptive activity were subjected to the next dose-effect relationship study.The results indicated five of them showed a hyperbolic curve, while one exhibited an inverted U-shaped dose response curve.And four compounds have pain-relieving potency four times superior to asipirin.5. Naloxone withdrawal syndromes addictive researchs of the selected compounds were demostrated on mice.The results showed that these compounds possessed no addictive effect.6. The optimized compounds exhibiting the best activity were chosen for pharmacokinetics study on beagles.The data revealed T1/2 is 0.5-0.9 h, Tmax is 1.0 h,Cmax is 1000-1200ng/L,AUC(0-t) is 2052ng h/L through intragastric administration,7. Finally, 3D-QSAR model based on APPRR193 pharmacophore alignment was built to analyze these compounds, the predicted power of model was validated by arylpiperazines focused virtual library and further compound design.