Gualtieri F, Bottalico C, Calandrella A, Dei S, Giovannoni M P, Mealli S, Romanelli M N, Scapecchi S, Teodori E, Galeotti N
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
J Med Chem. 1994 May 27;37(11):1712-9. doi: 10.1021/jm00037a023.
Further modifications of the leads ((R)-(+)-hyoscyamine and (p-chlorophenyl)propionic acid alpha-tropanyl ester), which show analgesic and nootropic activities as a consequence of increased central presynaptic ACh release, are reported. 2-Phenoxy- and 2-(phenylthio)alkanoic acid esters showed the best results. Several members of these classes possess analgesic properties which are comparable to that of morphine and at the same time are able to reverse dicyclomine-induced amnesia. Confirmation was found that the mechanism of action is due to an increase in ACh release at central muscarinic synapses and that both auto- and heteroreceptors controlling ACh release are very likely involved. According to the results obtained with (R)-(+)-hyoscyamine, analgesic activity is stereochemistry dependent, since the R-(+)-enantiomers are always more efficacious than the corresponding S-(-)-ones. On the basis of their potency and acute toxicity, compounds (+/-)-28 (SM21) and (+/-)-42 (SM32) were selected for further study.
据报道，对一些先导化合物（（R）-（+）-莨菪碱和（对氯苯基）丙酸α-托烷酯）进行了进一步修饰，这些化合物由于中枢突触前乙酰胆碱释放增加而表现出镇痛和促智活性。2-苯氧基和2-（苯硫基）链烷酸酯显示出最佳结果。这些类别中的几个成员具有与吗啡相当的镇痛特性，同时能够逆转双环维林诱导的失忆。已证实其作用机制是由于中枢毒蕈碱突触处乙酰胆碱释放增加，并且控制乙酰胆碱释放的自身受体和异源受体很可能都参与其中。根据用（R）-（+）-莨菪碱获得的结果，镇痛活性取决于立体化学，因为R-（+）-对映体总是比相应的S-（-）-对映体更有效。基于它们的效力和急性毒性，选择了化合物（±）-28（SM21）和（±）-42（SM32）进行进一步研究。
