Specificity in enzyme inhibition. 3. Synthesis of 5-substituted 2,2-dimethyl-4-imidazolidinones as inhibitors of tyrosine decarboxylase and histidine decarboxylase.

2,2-Dimethyl-4-imidazolidinone derivatives of the alpha-amino acids DL-phenylglycine (1), DL-phenylalanine (2), L-tyrosine (3), L-histidine (4), and L-tryptophan (5) were prepared in order to assess their specificity in inhibiting amino acid decarboxylases. Treatment of th alpha-aminonitriles with acetone in the presence of base and heat or treatment of the alpha-amino amides with acetone gave the title compounds in 48-85% yield. The compounds afforded moderate ability to inhibit the decarboxylation of L-phenylalanine, L-tyrosine, or L-histidine in vitro, using crude enzymes. 3 was a better inhibitor of tyrosine decarboxylase (S. faecalis) than 2. 4 and 5 were comparable to 3 in inhibiting tyrosine decarboxylase. 4 was more selective in inhibiting purified histidine decarboxylase (Cl. welchii) than 5, which was inactive. 4 was inactive against fetal rat histidine decarboxylase in vitro.

A conformational study of beta-phenethanolamine receptor sites. 8. Pharmacological study of 3-isopropylamino-2-phenyl-trans-2-decalols.

Two N-isopropylnorephedrines and their four possible decalol analogs were compared pharmacologically. Four of the six compounds at a concentration of 1 x 10(-4) M caused a potentiation of D(-)-norepinephrine (NE) contraction of the rat vas deferens and increased the maximal response of the preparation to NE. Pretreatment in vivo with reserpine (5 mg/kg ip) 24 hr before the experiment in vitro did not change these effects. At a concentration higher than 1 x 10(-3) M all of the decalin analogs antagonized the effects of NE. All of the analogs lowered the dog blood pressure briefly. The lowering of blood pressure was augmented by alpha-adrenergic blockade and was not changed by beta-adrenergic blockade, atropine, or a ganglionic blocking agent. Tachyphylaxis was not observed. The spontaneous contraction of isolated rabbit atria was depressed by the substances at concentrations of 1 x 10(-4)-1 x 10(-3) M. Catecholamine uptake in rat vas deferens was lowered by the substances and all of them produced a release of catecholamines from vas deferens. By virtue of the conformational rigidity of the decalols, possible inferences concerning the stereochemical aspects of the interaction of the ephedrine analogs with adrenergic neurone-receptor sites are discussed.

Synthesis and blood pressure lowering activity of benzylic ethers of 2-diethylaminoethanol and a related diamine.

Based upon the unpublished finding that 3'-hydroxy-4'-(beta-diethylaminoethoxy)-3',4'-dihydroseselin possessed a potent blood pressure lowering effect in the cat at a dose of 1 mg/kg, the present study examined the activities of several related compounds. These compounds were derived by dissection of the parent compound to give four benzylic ethers of 2-diethylaminoethanol and a diamine, derived by replacing the ether oxygen of the parent compound with an N--CH3 function. The simplest compounds were the benzyl and 2,6-dimethoxybenzyl ethers of the aminoalcohol. Closely related to the benzyl compound was a congener with a hydroxymethyl group on the benzylic carbon. The beta-diethylaminoethyl ether of 4-chromanol was the most complex of the ethers. The blood pressure measurements were carried out on male cats and compared to papaverine hydrochloride as a standard. In all cases, the most potent blood pressure lowering activity resided in the parent compound, which was not greatly superior to the diamine but substantially more active than the other compounds.