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The role of hydrophobic interactions in inhibiting the relatively specific enzymatic reactions of five enzyme systems by series of congeneric drugs has been illustrated by the use of substituent constants and regression analysis. The inhibition of lipoxygenase by alcohols, the inhibition of D-amino acid oxidase by maleimides, and the inhibition of hydroxyindole-o-methyltransferase by N-acyltryptamines are found to be linearly dependent on the lipohydrophilic character of the inhibitors (log P or π). The inhibition of carbonic anhydrase by sulfonamides is found to be linearly dependent on the log P and Hammett's σconstant. For monoamine oxidase inhibition by substituted β-carbolines, a parabolic equation of log P gives the most significant correlation. The ideal lipohydrophilic character (log Po) for maximum inhibition is found to be 2.74.

Data presented show that lactams, which have the resonating structure commonly associated with CNS depressants and CNS stimulants, have significant CNS activities. Results of preliminary testing show that lactams of medium ring size and lacking N-substitution are fairly potent CNS stimulants. The acute lethal toxicity (log 1/C) of four CNS stimulants of the lactam type is found to be highly correlated with log P, where P is the 1-octanol-water partition coefficient for the compound. The rate of respiration in mice depressed with sodium pentobarbital is stimulated by 2-azacyclononanone, and the rate and depth of respiration were increased by 2-azacyclooctanone in dogs anesthetized with sodium pentothal. Both 2-azacyclooctanone and 2-azacyclononanone are capable of reducing considerably the sodium pentobarbital sleeping time in mice. At higher doses, the CNS stimulant effects of these drugs are manifested by convulsions. For 2-azacyclooctanone, the convulsant ED50 is about 37 mg./kg. and the LD50 is about 300 mg./kg. Direct evidence for CNS stimulation by 2-azacyclooctanone was obtained by recording changes in EEG patterns in artificially ventilated dogs paralyzed with d-tubocurarine. Diphenylhydantoin is much less effective as an antagonist to the convulsant actions of 2-azacyclooctanone than sodium pentobarbital. This finding, taken together with the tonic-clonic convulsions produced by this drug, strongly suggests that, like nikethamide and pentylenetetrazole, the site of action for its CNS effects is subcortical and supraspinal. The conclusion is drawn that the resonating moiety shown here confers upon many compounds CNS-stimulant activities.