ABSTRACT
A number of analogs of the tripeptide L-prolyly-L-leucylglycinamide (1) were synthesized and evaluated in the Dopa potentiation and oxotremorine antagonism tests. The replacement of the glycinamide residue with either the glycine methylamide, glycine, aminoacetonitrile, amino-2-propanone, semicarbazide, or beta-alaninamide residues resulted in a loss of activity in both tests. A 1:1 mixture of L-prolyl-L-leucyl-(-)-thiazolidine-2-carboxamide (8) and L-prolyl-L-leucyl-(+)-thiazolidine-2-carboxamide (9) showed marked activity in the Dopa potentiation test but was unable to antagonize the tremors induced by oxotremorine. L-Prolyl-L-leucyl-L-prolinamide (11), on the other hand, was active in the oxotremorine antagonism test but inactive in the Dopa potentiation test. The replacement of the pyrrolidine ring of 1 with either a thiazolidine or cyclopentane ring system caused a loss of activity. The cyclopentanecarboxylic acid analogue 13, however, was found to have moderate activity in the serotonin potentiation test.
Subject(s)
Dihydroxyphenylalanine/pharmacology , MSH Release-Inhibiting Hormone/chemical synthesis , Oxotremorine/antagonists & inhibitors , Aggression/drug effects , Animals , Behavior, Animal/drug effects , Drug Synergism , Humans , MSH Release-Inhibiting Hormone/pharmacology , Male , Mice , Mice, Inbred ICR , Motor Activity/drug effects , Pargyline/pharmacology , StereoisomerismABSTRACT
A series of cis and trans bicyclic lactones was prepared as congeners of podophyllotoxin (1) and evaluated as antimitotic agents both in cell cultures grown in vitro and in an in vitro protein binding assay. All compounds displayed insignificant activity-a result which may reflect insufficient structural similarity to podophyllotoxin or which may be interpreted as in agreement with previous observations of the stereochemical requirements for antimitotic activity defined for 1.
Subject(s)
Cyclohexanecarboxylic Acids/chemical synthesis , Mitosis/drug effects , Podophyllotoxin/analogs & derivatives , Animals , Bone Marrow/metabolism , Bone Marrow Cells , Brain/metabolism , Cattle , Clone Cells/metabolism , Colchicine/metabolism , Cyclohexanecarboxylic Acids/pharmacology , Depression, Chemical , Hematopoiesis/drug effects , In Vitro Techniques , Lactones/chemical synthesis , Lactones/pharmacology , Mast-Cell Sarcoma/metabolism , Podophyllotoxin/pharmacology , Protein Binding/drug effects , Sarcoma, Experimental/metabolism , Tubulin/metabolismSubject(s)
Alanine/analogs & derivatives , Cell Wall/drug effects , Dipeptides/chemical synthesis , Alanine/chemical synthesis , Alanine/pharmacology , Bacillus subtilis/drug effects , Dipeptides/pharmacology , Enterococcus faecalis/drug effects , Escherichia coli/drug effects , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Salmonella typhimurium/drug effects , Staphylococcus aureus/drug effects , Streptococcus pyogenes/drug effectsABSTRACT
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.
Subject(s)
Carboxy-Lyases/antagonists & inhibitors , Histidine Decarboxylase/antagonists & inhibitors , Imidazoles/chemical synthesis , Tyrosine Decarboxylase/antagonists & inhibitors , Animals , Clostridium perfringens/enzymology , Enterococcus faecalis/enzymology , Fetus/enzymology , Imidazoles/pharmacology , In Vitro Techniques , Phenylalanine , RatsABSTRACT
Various 2- and 4-substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisquinolines were synthesized and evaluated as substrates and inhibitors of catechol O-methyltransferase (COMT). In addition, these compounds were tested for their ability to release norepinephrine-3H from mouse hearts in vivo. Methyl substituents in the 2 and/or 4 positions of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline had little effect on the interaction of these molecules with COMT. In general, the substrate kinetic (Km, Vmax) and inhibitory kinetic (Kis) properties toward COMT were similar for each of these compounds. In contrast, norepinephrine depleting activity showed more strict structural requirements. Methyl substituents in the 2 or 4 positions of the parent compound, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, eliminated the norepinephrine depleting activity. The interesting exception was 6,7-dihydroxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide, which was found to be more active than the parent molecule as a depleter of norepinephrine from mouse hearts.
Subject(s)
Isoquinolines/chemical synthesis , Animals , Catechol O-Methyltransferase Inhibitors , In Vitro Techniques , Isoquinolines/pharmacology , Kinetics , Liver/enzymology , Male , Mice , Myocardium/metabolism , Norepinephrine/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Three analogs of 6-aminodopamine were synthesized and tested for their ability to deplete the central nervous system of norepinephrine and dopamine. The compounds were analogs in which the aliphatic nitrogen of the ethyl side chain was substituted with dimethyl, isopropyl, and methyl groups. The first two compounds showed only very weak depletion of norepinephrine stores, while having no effect on dopamine levels. The third compound was not tested due to its instability.
Subject(s)
Brain/metabolism , Catecholamines/metabolism , Dopamine/analogs & derivatives , Animals , Dopamine/chemical synthesis , Dopamine/metabolism , Dopamine/pharmacology , Mice , Norepinephrine/metabolismABSTRACT
It is agreed that the neurotoxic action of 6-hydroxydopamine and 6-aminodopamine is related to their ease of oxidation. The initial oxidation products, the p-quinone and p-quinone imine, readily undergo 1,2-intracyclization. These reactions could represent an important loss of active neurotoxic agent available uptake. A variety of substituted 6-aminodopamine analogs was prepared and their formal potentials and cyclization rates were measured accurately. The effect of the balance of ease of oxidation vs. rate of cyclization on their neurotoxicity was examined. The results are in general accord with in vivo lifetimes for 6-hydroxydopamine and 6-aminodopamine in rat caudate nucleus.
Subject(s)
Dopamine/analogs & derivatives , Hydroxydopamines , Chemical Phenomena , Chemistry , Cyclization , Dopamine/metabolism , Half-Life , Hydroxydopamines/metabolism , Neurons/metabolism , Oxidation-Reduction , PotentiometryABSTRACT
Three 3,7-diazabicyclo[3.3.1]nonane derivatives (4) with a structural similarity to the analgetic agent azabicyclane (1) were prepared. The amino alcohol 4a was found to prefer a conformation wherein the six-membered ring to which the hydroxyl group is syn is in the boat form. These three compounds had increased basicity in comparison with 1 due to various forces stabilizing their monocationic states. Compounds 4a-c did not show analgetic activity at the dose levels tested.
Subject(s)
Analgesics/chemical synthesis , Aza Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Animals , Aza Compounds/pharmacology , Bridged Bicyclo Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic , Gastrointestinal Motility/drug effects , Mice , Molecular Conformation , Quinones/antagonists & inhibitors , Reaction Time/drug effects , Spasm/prevention & controlABSTRACT
The specificity of an antibody directed against d-(S)-methamphetamine (MA) was determined by competitive binding assay with more than 50 compounds-metabolites, homologs, and analogs of amphetamine. The antibody appears to be specific both for the side chain and the aromatic ring of d-(S)-amphetamine (A). The basic requirements for a compound to be bound to the antibody are (a) an aromatic ring, (b) a basic nitrogen, and (c) a two-carbon chain between the aromatic ring and the nitrogen. A transoid conformation for the phenethylamine skeleton is preferred. The interaction of the antibody with compounds differing from MA or A in side-chain substitutions was directly proportional to the closeness of their structure to MA and/or A. The antibody exhibited greatly reduced affinity for ring-substituted analogs of A; the p-hydroxy metabolite of A did not bind to the antibody. A radioimmunoassay of A is described; it was utilized to study the disposition of A in dogs.
Subject(s)
Amphetamines/immunology , Antibody Specificity , Methamphetamine/immunology , Amphetamines/pharmacology , Animals , Binding, Competitive/drug effects , Dextroamphetamine/blood , Dextroamphetamine/metabolism , Dogs , Female , Immune Sera/pharmacology , Molecular Conformation , Phenethylamines/pharmacology , Protein Binding/drug effects , Radioimmunoassay , Structure-Activity RelationshipABSTRACT
6-Aminodopamine (6-NH2DA) and various analogs of 6-NH2DA have been evaluated for their ability to inactivate purified catechol O-methyltransferase (COMT) in vitro. The inactivation of COMT by these agents could be prevented by including an antioxidant in the preincubation mixture or by excluding oxygen; however, catalase did not protect the enzyme from inactivation. Substrate protection studies and kinetic studies suggested that the loss of enzyme activity resulted from the alkylation of an amino acid residue at the active site of COMT by the quinoid types products which were generated upon air oxidation of 6-NH2DA. In addition, we have explored in more detail the reactivity toward COMT of specific intermediates in the oxidation pathways of 6-NH2DA by using various 6-NH2DA analogs. From the above studies we have concluded that 6-aminodopamine-p-quinone (6-NH2DAQ) is perhaps the most toxic species toward COMT. However, the aminochromes which are formed from 6-NH2DAQ are also effective in inactivating COMT. The results of these studies have provided a useful model system for observing the interaction of 6-NH2DA and its oxidation products with proteins; in addition, it has provided additional insight into the topography of the active site of COMT.
Subject(s)
Affinity Labels/pharmacology , Catechol O-Methyltransferase/metabolism , Dopamine/analogs & derivatives , Aerobiosis , Animals , Antioxidants/pharmacology , Catalase/pharmacology , Depression, Chemical , Dopamine/pharmacology , In Vitro Techniques , Kinetics , Liver/enzymology , Male , Oxidation-Reduction , RatsABSTRACT
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.
Subject(s)
Ethanolamines , Naphthols/pharmacology , Phenethylamines , Receptors, Drug , Animals , Blood Pressure/drug effects , Dogs , Female , In Vitro Techniques , Male , Molecular Conformation , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Myocardial Contraction/drug effects , Naphthols/chemical synthesis , Norepinephrine/metabolism , Norepinephrine/pharmacology , Phenylpropanolamine/analogs & derivatives , Propylamines/pharmacology , Rabbits , Rats , Vas Deferens/drug effects , Vas Deferens/metabolismABSTRACT
The base- and cholinestrase-catalyzed hydrolyses of the following optically active analogs of acetylcholine were studied: 3 (a)-trimethylammonium-2(a)-acetoxy-trans-decalin iodide, threo- and erythro-alpha, beta-dimethylacetylcholine iodide, alpha-methylacetylcholine, and beta-methylacetylcholine. Evidence that the optimum dihedral +N-C-C-O angle in the transition state for acetylcholinesterase hydrolysis of acetylcholine analogs is positive and anticlinal is given. The data obtained suggest that acetylcholine undergoes a geometrically flexible mode of attachment to the enzyme.
