Gualtieri F, Conti G, Dei S, Giovannoni M P, Nannucci F, Romanelli M N, Scapecchi S, Teodori E, Fanfani L, Ghelardini C
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
J Med Chem. 1994 May 27;37(11):1704-11. doi: 10.1021/jm00037a022.
Previous studies have shown that (R)-(+)-hyoscyamine has analgesic activity as a consequence of increased ACh release following antagonism of central muscarinic autoreceptors. Since the enhancement of central cholinergic transmission could be beneficial for cognitive disorders, we manipulated (R)-(+)-hyoscyamine, synthesizing several derivatives of tropic and 2-phenylpropionic acids, with the aim of obtaining drugs which are able to increase ACh release and consequently to show analgesic and nootropic activities. The results showed that several new compounds are indeed potent analgesics (with an analgesic efficacy comparable to that of morphine) and that the most potent one ((+/-)-19, PG9) also has remarkable cognition-enhancing properties. Our study confirmed that the mechanism of action involves ACh release even if it is still unclear whether only muscarinic autoreceptors or, also, heteroreceptors are involved.
先前的研究表明，（R）-（+）-莨菪碱具有镇痛活性，这是其中枢毒蕈碱自身受体拮抗后乙酰胆碱释放增加的结果。由于增强中枢胆碱能传递可能对认知障碍有益，我们对（R）-（+）-莨菪碱进行了改造，合成了几种托品酸和2-苯基丙酸的衍生物，目的是获得能够增加乙酰胆碱释放并因此显示出镇痛和促智活性的药物。结果表明，几种新化合物确实是有效的镇痛药（镇痛效果与吗啡相当），最有效的一种（（+/-）-19，PG9）也具有显著的认知增强特性。我们的研究证实，其作用机制涉及乙酰胆碱释放，尽管目前尚不清楚是仅涉及毒蕈碱自身受体还是也涉及异源受体。
