螺环哌嗪类铵盐类新型镇痛药物研究

N1, N1-Dimethyl-N4-phenylpiperazinium iodide (DMPP) is a well-known nicotinic agonist that doesn't fit any proposed pharmacopoeia for nicotinic binding. This quaternary salt does not cross the blood brain barrier (BBB) as required for drugs useful to treat neurodegenerative diseases, however, it exhibits significant analgesic activity. Therefore, it represents a unique ligand among the hundreds of nicotinic agonists studied in the past decades. Recently, more attention has been directed to the study on this kind of compounds. In this study, spiropiperazinium compounds 100580 and B-018 were selected as lead compounds, and 64 analogues of them, divided into four kinds, were designed, synthesized and evaluated for their analgesic activity. Three compounds were found to show excellent activity among screened compounds. The compound 97-9-G4 was choose to further study from above three compounds based on the toxicity results. It is revealed that the analgesic activity of 97-9-G4 through the side-ventricles injection is 4000 times of that through subcutaneous jection, though two injecting forms all display excellent analgesic. The action mechanism maybe related with one kind of opioid receptor subtypes, because it can be blocked by Naloxone, an opioid receptor agtagonist. However, compared with morphine, morphine showed significant addiction at 10mg/kg, 97-9-G4 doesn't appear any addiction at the dose 160mg/kg. All above results are very important for the deeply study on the quaternary ammonium analgesics.

螺环哌嗪季铵盐是我们发现的一类结构全新的镇痛化合物，其中有两个化合物活性很好。据最近专利报道，桥环哌嗪类化合物既具有镇痛活性，又具有非成瘾性，与螺环哌嗪季铵盐的结构很相似。本研究以发现的两个活性很好的化合物为先导，结合桥环哌嗪的结构特征对其进行结构改造，可望发现镇痛活性更强，非成瘾性的化合物。然后，再开发出一类新药。.......