Various CNS activities, such as antielectroshock, antipentylenetetrazol-induced seizures, muscle relaxant, and acute lethal toxicity, of different types of compounds were correlated with three physicochemical parameters, namely lipophilicity (log P), dipole moment, and steric considerations (EJ. The relatively narrow range of log Po (2.0 f 0.7) for compounds possessing a polar group, e.g., arnido. thioamido, keto, or alcoholic function,strongly suggests that the rate-limiting step for these different CNS-acting drugs is probably the same, namely the penetration of the tightly packed neuroglial cells (the socalled blood-brain barrier). Negative dependence of the anticonvulsant or CNS depressant activity on the dipole moment and positive dependence of the stirnulatory CNS toxicity on the same parameter were found to be statistically significant. Entirely different sites and mechanisms of action appear to be evident from the very low estimated log Po values of lactones and 2-sulfamoylbenzoates for their CNS depressant activities. The CNS activity of five lactones was studied in mice. While y-butyrolactone caused dosage-dependent sedation and sleep at 100-1OOO mg./kg., no loss of the righting reflex was observed for a-methyl-y-butyrolao tone (lo00 mg./kg.), 7-valerolactone (2OOO mg./kg.), d-valerolactone (750 mg./kg.), and 7-heptalactone (lo00 mg./kg.). After intraperitoneal injection of y-valerolactone and 7-heptalactone, paralysis of the hind legs was observed, indicating local anesthetic activity on the peripheral nervous system. Keyphrases 0 CNS activity-investigation of structural requirements 0 Structure-activity relationships-structural requirements for CNS activity 0 y-Butyrolactone-CNS depressant activity, effect of lipophilicity 0 Lipophilicity-relationship to CNS activity