substituents should protect better and more effectively preclude interaction with a bioactive macromolecule. Rationalization t, because it is a combination of a and b, also is apparently disputed.
The fact that the N,N-dialkylamides are as potent as the N-monoalkylamides could be rationalized as follows: (a) better distribution to the receptor because of the increased hydrocarbon content, (b) a substantial amount of N-dealkylation, (c) increased hydrophobic interactions. Upon examination however, rationalizations a and c must be discarded. for on the basis of these, N-monoalkylation should not have decreased activity. It thus appears that N-dealkylatim may be a factor.
If this is the case the three rationalizations previously set forth with respect to the effect upon activity of mono-N-aIkylation may be valid. These rationalizations are consonant with a sterically accessible amide function interacting with the bioactive macromolecule. The interaction possibly involves hydrogen bonding through the media of an amide hydrogen atom.
Conclusions
The following compounds: %ethyl-2-propylcyanoacetamide; N-methyl-2,2dipropylcyanoacetamide; N-methyl-2-ethyl-Zpropylcyanoacetamide; N-dimethyl-2ethyl-2-propylcyanoacetamide; 2,2-diethylcyanoacetamide6; N -methyl -2,2diethyl-cyanoacetamide6 ; and N-dimethyl-2,%diethylcyanoacetamide have been found active when subjected to testing by an electroshock method using rats. The median effective dose (EDw, mg./kg.) of each active drug was determined and reported. The least toxic and most active compounds were (EDwLDw,~ TI, respectively) : N-methyl-2,2-dipropylcyanoacetamide, 70, 450, 6.4; 2-ethyl-2-propylcyanoacetamide, 71, 575,S.l; 2,2diethylcyanoacetamide, 170, I, OOO, 5.9.
Approximate.
6 See Footnote a, Table I. 1535 Convulsive tendencies and/or lack of activity prevented quantification of the seven drugs: Npropyl-2-ethyl-Zpropylcyanoacetamide; N-propyl-2,Zdiethylcyanoacetdde; 1-(2cyano -2ethyl-butyry1)-piperidine; 1-(2-cyano -2 -ethylvalery1)piperidine; 1-(2-cyano-%ethylbutyryl)-pyrrolidme; 1-(2 cyanoethylvaleryl)pyrrolidine; and 4 -(2cyano-2-ethylbutyryl)-mwpholine. Qualitative observations were made and recorded. SUSTAINED-RELEASE product has been defined