A series of aminomethyl-substituted cyclic imides (II) based on the 2,5-pyrrolidinedione (X = CH2, succinimide) and 2,4-imidazolidinedione (X = NH, hydantoin) ring systems have been prepared. The compounds were designed on the basis of a potential interaction in the gamma-aminobutyric acid (GABA) neurotransmitter system and evaluated for anticonvulsant activity. The 3-(aminomethyl)-2,5-pyrrolidinediones were prepared by a dehydration procedure beginning with N-benzyl-2-(aminomethyl)succinic acid, whereas the 3-(aminomethyl)-3-methyl-2,3-pyrrolidinediones were best obtained by fusion of the amine salts of 2-(aminomethyl)-2-methylsuccinic acid. The hydantoin derivative, 5-(aminomethyl)-5-methyl-2,4-imidazolidinedione, was obtained by standard procedures. Although none of the compounds tested showed significant activity against convulsions induced by pentylenetetrazole (PTZ), some showed significant activity against maximal electroshock seizures in mice. Possible reasons for the lack of anti-PTZ activity and directions for further testing are discussed.
The antagonist activity of the title compound 2 and some open chain and cyclic analogs on glycerol release from adipose tissue and incorporation of mevalonate-#-1"^into nonsaponifiable products of rat liver homogenate in vitro is discussed. Greater structural specificity was observed for the inhibition of cholesterol biosynthesis than for inhibition of lipolysis. A proposed mechanism for the antilipolytic effect of 2 is described.
Studies leading to, and the synthesis of, DL-6-chlorochroman-2-carboxylic acid (2) and DL-2-methyl-6-chlorochroman-2-carboxylic acid (3) are presented. These compounds are cyclic analogs of the hypocholesterolemic and hypolipidemic agent a-(4-chlorophenoxy)-a-methylpropiomc acid (1). Preliminary results on their ability to antagonize glycerol release from rat epididymal fat pads and inhibit mevalonate-S-^C incorporation into nonsaponifiable material of rat liver homogenate are discussed. Participant, Summer, 1970. (2) (a) D.
1,2,3,4-Tetrahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (20) and cis- and trans-1,2,3,4,4a,10b-hexahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (3a and 3b) were synthesized. The design of 3b was based on the proposal that the active conformation of cocaine is one in which the phenyl and amino groups are arranged in a manner that will superimpose upon a beta-phenethylamine in a trans-staggered conformation. The compounds were compared with cocaine and tropacocaine for their ability to inhibit uptake of [3H]norepinephrine by rat brain synaptosomal preparations. The test compounds (IC50 = 3.2 X 10(-4) M, 20; 6.5 X 10(-4) M, 3a; and 3.2 X 10(-4) M, 3b; respectively) were considerably weaker than cocaine (IC50 = 5.8 X 10(-7) M) and tropacocaine (IC50 = 5.6 X 10(-6) M). Compound 3b showed selectivity at 1 X 10(-5) M for inhibiting the uptake of norepinephrine (36%). It inhibited dopamine (3%) and serotonin (0%) uptake to a much lesser extent, if at all, at this concentration.
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