CNS activity of thalidomide was compared with that of 5 analogs modified in the phthalimide or 2,6-dioxopiperidine moiety. All compounds had a qualitatively comparable profile of CNS-depressant actions. In low dosages spontaneous motor activity was depressed, threshold of barbiturate anaesthesia was lowered, and isolation-induced aggression was inhibited. All compounds suppressed tonic convulsions induced by maximum electroshock. Only at high dosages muscle tone and body temperature were lowered. Protection against nicotine lethality revealed antagonistic activity at central nicotinergic synapses. Corresponding depression of peripheral ganglionic transmission was indicated by mydriatic and antidiarrhoeal activity. While thalidomide, supidimide, EM 8, and EM 255 did not induce anaesthesia up to highest or lethal-toxic doses, EM 136 and EM 12 in accordance with common sedative-hypnotic drugs induced loss of righting reflex at high dosages. EM 136 differs from thalidomide only in that one oxygen group at the piperidine moiety is missing. This finding indicates that a minor structural change shifts CNS depression towards anaesthetic properties. A clearcut relation between structure and teratogenic activity had been established in this group of compounds, whereas CNS-depressant efficacy could not be unequivocally related to particular structural features.