Palacios J M, Bolliger G, Closse A, Enz A, Gmelin G, Malanowski J
Eur J Pharmacol. 1986 Jun 5;125(1):45-62. doi: 10.1016/0014-2999(86)90082-8.
The effects of the compound RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide) in a number of in vitro and in vivo test systems for muscarinic cholinergic activity were analyzed and compared to those of classical muscarinic receptor agonists. In radioligand binding assays RS 86 presented high nanomolar apparent affinity only for sites labeled by 3H-muscarinic receptor agonists while its apparent affinity for sites labeled by 3H-muscarinic receptor antagonists including [3H]QNB, [3H]NMS and [3H]pirenzepine was in the micromolar range. RS 86 had no or only low affinity (IC50 greater than 10 microM) for other neurotransmitter or drug receptor sites. The compound induced scopolamine-sensitive contractions of the isolated guinea-pig ileum showing a pD2 of 6 in this model. In the isolated rat superior cervical ganglion RS 86 was also an agonist with a pD2 of 6.7. When given to mice or rats by different routes RS 86 induced central and peripheral effects typical of a muscarinic receptor agonist, such as hypothermia, tremor, mydriasis, salivation, lacrimation, diarrhoea and modification of behavior as observed in an open field. In several of these tests RS 86 was about 10 times less potent than oxotremorine but more potent than arecoline, pilocarpine, aceclidine or the compound (cis) AF-30. The ED50 values for some central effects, including the induction of hypothermia and alert non-mobile behavior were lower than those for tremor and peripheral effects. Some of the effects lasted for up to 6 h, depending on the dose. Finally, RS 86 administration resulted in modifications of brain acetylcholine turnover and high affinity choline uptake typical of a central muscarinic receptor agonist. Taken together these results demonstrate clearly that RS 86 is a potent, centrally acting, selective muscarinic receptor agonist. RS 86 appears to be an adequate tool for the clinical examination of the cholinergic hypothesis of Alzheimer's disease.
分析了化合物RS 86（2-乙基-8-甲基-2,8-二氮杂螺[4,5]癸烷-1,3-二酮氢溴酸盐）在多种用于毒蕈碱胆碱能活性的体外和体内测试系统中的作用，并与经典毒蕈碱受体激动剂的作用进行了比较。在放射性配体结合试验中，RS 86仅对由3H-毒蕈碱受体激动剂标记的位点表现出高纳摩尔的表观亲和力，而其对由3H-毒蕈碱受体拮抗剂标记的位点，包括[3H]QNB、[3H]NMS和[3H]哌仑西平的表观亲和力处于微摩尔范围。RS 86对其他神经递质或药物受体位点无亲和力或仅有低亲和力（IC50大于10 microM）。该化合物能诱导豚鼠离体回肠产生对东莨菪碱敏感的收缩，在此模型中显示出的pD2为6。在离体大鼠颈上神经节中，RS 86也是一种激动剂，pD2为6.7。当通过不同途径给予小鼠或大鼠时，RS 86会诱导出典型的毒蕈碱受体激动剂的中枢和外周效应，如体温过低、震颤、散瞳、流涎、流泪、腹泻以及在旷场试验中观察到的行为改变。在其中一些试验中，RS 86的效力比氧化震颤素低约10倍，但比槟榔碱、毛果芸香碱、醋克利定或化合物（顺式）AF-30更强。一些中枢效应的ED50值，包括体温过低和警觉不动行为的诱导，低于震颤和外周效应的ED50值。某些效应可持续长达6小时，具体取决于剂量。最后，给予RS 86会导致脑乙酰胆碱周转率和典型的中枢毒蕈碱受体激动剂的高亲和力胆碱摄取发生改变。综合这些结果清楚地表明，RS 86是一种强效的、具有中枢作用的、选择性毒蕈碱受体激动剂。RS 86似乎是用于阿尔茨海默病胆碱能假说临床检验的合适工具。
