Clarke R L, Gambino A J, Pierson A K, Daum S J
J Med Chem. 1978 Dec;21(12):1235-42. doi: 10.1021/jm00210a013.
Tropanes 4 bearing an exo aromatic group on carbon-2, an endo-carbomethoxy group on carbon-3, and either a methyl group or a hydrogen on the nitrogen were found to be narcotic antagonists which were devoid of demonstrable analgesic activity. The activity resided in the 1S enantiomer. Compound 4 (R = m-hydroxyphenyl) showed an AD50 of 0.37 mg/kg sc and 1.8 mg/kg po (rats) as an antagonist in the Harris-Pierson modification of the D'Amour-Smith test. The tropane esters for this study were prepared by a Grignard reaction which gave essentially complete 1,4-addition in the absence of copper salts. Nearly equal quantities of esters epimeric at carbon-3 were formed.
发现2位带有外芳香基团、3位带有内碳甲氧基且氮上带有甲基或氢的托烷4是麻醉拮抗剂，没有可证实的镇痛活性。活性存在于1S对映体中。化合物4（R = 间羟基苯基）在哈里斯-皮尔森改良的达莫尔-史密斯试验中作为拮抗剂，皮下给药的半数有效剂量（AD50）为0.37毫克/千克，口服给药为1.8毫克/千克（大鼠）。本研究中的托烷酯是通过格氏反应制备的，该反应在没有铜盐的情况下基本完全发生1,4-加成。形成了几乎等量的在3位差向异构的酯。
