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Biomedical subjects

F I Carroll

Publications and source records attributed to F I Carroll.

At least 163 records · Page 9Linked to original sources
PubMed1990

[3H]WIN 35,065-2: a ligand for cocaine receptors in striatum.

[3H]WIN 35,065-2 binding to striatal membranes was characterized, primarily by centrifugation assay. Like [3H]cocaine, [3H]WIN 35,065-2 binds to both high- and low-affinity sites. [3H]WIN 35,065-2, however, exhibits consistently higher affinities than [3H]cocaine. Saturation experiments indicate a low-affinity binding site with an apparent KD of approximately 160 nM and a Bmax of 135 fmol/mg of tissue. A high-affinity site has also been identified with an apparent KD of 5.6 nM and a Bmax of 5.2 fmol/mg of tissue. The specific-to-nonspecific binding ratios with [3H]WIN 35,065-2 were higher than with [3H]cocaine in both centrifugation and filtration assays. Pharmacological characterization suggests that [3H]WIN 35,065-2 binds to the dopamine transporter. Mazindol, GBR 12909, nomifensine, and (-)-cocaine are potent inhibitors of [3H]WIN 35,065-2 binding. In contrast, the norepinephrine transporter ligand desipramine is a weak inhibitor, and the serotonin transporter ligand citalopram does not inhibit binding. The effect of sodium on binding was examined under conditions in which (a) the low-affinity site was primarily (87%) occupied and (b) approximately 50% of both sites were occupied. The results indicate that both sites are sodium dependent. Injection of 6-hydroxydopamine into the striatum results in a significant loss of both high- and low-affinity sites, a finding suggesting that both sites are on dopaminergic nerve terminals. Taken together, these data are consistent with the presence of multiple cocaine binding sites associated with the dopamine transporter.

Animals↗
PubMed1988

Synthesis, absolute configuration, and molecular modeling study of etoxadrol, a potent phencyclidine-like agonist.

Etoxadrol (2a), one of the eight possible optical isomers of 2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane, was synthesized from (S,S)-1-(2-piperidyl)-1,2-ethanediol, which was obtained from cleavage of dexoxadrol (1a, (S,S)-2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane). The absolute configuration of etoxadrol hydrochloride, a phencyclidine-like compound biologically, was determined to be 2S, 4S, and 6S at its three chiral centers by single-crystal X-ray analysis. Epietoxadrol (2b), epimeric with etoxadrol at the C-2 center, was also obtained from the synthesis. This much less potent enantiomer has the 2R,4S,6S configuration. The affinity of etoxadrol to the phencyclidine binding site was found to be comparable to that of phencyclidine itself and was 35 times more potent than its epimer, epietoxadrol. Three diastereomeric mixtures were prepared that had low affinity for the phencyclidine site. In studies of the discriminative stimulus properties of these compounds, it was found that only etoxadrol substituted for the phencyclidine stimulus. With use of computer-assisted molecular modeling techniques, a hypothetical phencyclidine binding site model has been developed that, unlike our former hypothesis based on Dreiding models, correctly predicts the higher affinity of etoxadrol and the lesser affinity of epietoxadrol for the phencyclidine site.

Animals↗
PubMed1988

1,2,4-Trioxanes as potential antimalarial agents.

A number of 1,2,4-trioxanes were prepared and tested for antimalarial activity in search of a simplified analogue of the naturally occurring antimalarial qinghaosu. The compounds were assayed in an in vitro system for antimalarial activity against chloroquine-susceptible and chloroquine-resistant strains of Plasmodium falciparum. The most active compounds were methyl 2-(2,4a-epidioxy-4a,5,6,7,8,8a-hexahydro-5,5,8a-trimethyl-2H-1-benzop yra n-2-yl) acetate (3b), which showed IC20's of 96 and 39 ng/mL, respectively, and 2,4a-epidioxy-3,4,4a,5,6,7,8,8a-octahydro-2-[2-(benzoyloxy)propyl]-5,5,8 a- trimethyl-2H-1-benzopyran (12), which showed IC50's of 24 and 99 ng/mL, respectively. For comparison, qinghaosu exhibits an IC50 of 1 ng/mL for both strains.

Animals↗
PubMed1988

Peptide derivatives of primaquine as potential antimalarial agents.

Three peptide derivatives of primaquine were synthesized. The compounds were tested for radical curative antimalarial activity against Plasmodium cynomolgi in rhesus monkeys and blood schizonticidal antimalarial activity against Plasmodium berghei in mice. All three peptide derivatives showed activity against P. cynomolgi greater than that expected for the primaquine content of each prodrug. The toxicity of one of the peptide derivatives was less than that of primaquine in mice.

Animals↗
PubMed1987

6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent.

The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block alpha-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.

Acetylcholine↗
PubMed1987

Endoperoxides as potential antimalarial agents.

A number of mono- and bicyclic endoperoxides were prepared and tested for antimalarial activity in search of a simplified analogue of the 5-oxygen-substituted 1,2,4-trioxane ring structure of the naturally occurring antimalarial qinghaosu. The compounds were assayed in an in vitro system for antimalarial activity against chloroquine-susceptible and chloroquine-resistant strains of P. falciparum. The most active compound in this assay was 2-[((butyloxy)-carbonyl)oxy]-1,1,10-trimethyl-6,9-epidioxy-delta 7-octalin (17a), which showed an IC50 of 100 and 57 ng/mL, respectively. For comparison, qinghaosu exhibits a mean IC50 less than 3.4 ng/mL.

Animals↗
PubMed1986

Enzymatic synthesis of a false cholinergic neurotransmitter: diethylaminoethyl acetate as a muscarinic agonist analog of acetylcholine.

Diethylaminoethyl acetate, an acetylcholine analog, was formed upon the incubation of diethylaminoethanol and acetyl-CoA with bovine brain choline acetyltransferase (acetyl-CoA: choline O-acetyltransferase; EC 2.3.1.6). The new product co-chromatographed with authentic diethylaminoethyl acetate on thin layer plates, and its formation was proportional to the duration of incubation and enzyme concentrations. When tested on guinea-pig ileum, diethylaminoethyl acetate was found to be an agonist with an ED50 of 1.3 X 10(-4) M, compared to an ED50 of 2.0 X 10(-7) M for acetylcholine. The contraction of guinea-pig ileum induced by diethylaminoethyl acetate was blocked by atropine. Moreover, diethylaminoethyl acetate induced a secretion of alpha-amylase from isolated pancreatic acini cells; this effect was also blocked by atropine. It is entirely possible that diethylaminoethyl acetate can be a false cholinergic transmitter generated in vivo when drugs such as aprophen or procaine are administered to animals, since either of these drugs can undergo enzymatic hydrolysis to generate diethylaminoethanol. A method for the synthesis of radioactive diethylamino [1,2-14C]ethyl acetate was also described.

Acetylcholine↗
PubMed1986

4,5-Disubstituted primaquine analogues as potential antimalarial agents.

Three 4,5-disubstituted primaquine analogues were synthesized and evaluated for radical curative activity against Plasmodium cynomolgi in rhesus monkeys. One of the compounds showed moderate activity; however, none of the three compounds were as active as the lead compounds 5-methoxy-4-methylprimaquine and 4-(methoxy-methyl)-5-[m-(trifluoromethyl)phenoxy]primaquine.

Animals↗
PubMed1985

4-substituted 5-[m-(trifluoromethyl)phenoxy]primaquine analogues as potential antimalarial agents.

Five 4-substituted 5-[m-(trifluoromethyl)phenoxy]primaquine analogues were synthesized and tested for radical curative activity against Plasmodium cynomolgi in Rhesus monkeys and for blood schizonticidal antimalarial activity against Plasmodium berghei in mice. In addition, they were evaluated for causal prophylactic antimalarial activity against Plasmodium berghei yoelii in mice. One compound, 4-ethyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2b), showed radical curative activity equivalent to 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2a). A second compound showed radical curative activity slightly less than 2a and 2b; the remaining three compounds were not active against P. cynomolgi. All five compounds showed much higher blood schizonticidal activity and less toxicity than primaquine; however, none of the compounds were as active as 2a. Three of four compounds tested showed high activity against P. berghei yoelii.

Animals↗
PubMed1985

Sulfur-interrupted 8-amino side chain analogues of 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine as potential antimalarial agents.

Two isomeric sulfur-interrupted 8-amino side chain analogues of 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2) were prepared and tested for antimalarial activity. The compounds were evaluated for blood schizonticidal activity against Plasmodium berghei in mice and radical curative activity against Plasmodium cynomolgi in rhesus monkeys. In addition, they were evaluated for causal prophylactic activity against Plasmodium berghei yoelii in mice. Both compounds were more active and less toxic than primaquine in the P. berghei screen. One of the compounds showed radical curative activity similar to primaquine but was less active than 2. One of the compounds was active at 160 mg/kg in the P. berghei yoelii screen; the other was not active.

Aminoquinolines↗
PubMed1984

Solution conformations of barbituric acid derivatives: a 3J(13C,1H) NMR study.

The conformations of the 5-alkyl chains of 5,5-dialkylbarbituric acid derivatives in polar and nonpolar media were determined from the magnitudes of the vicinal heteronuclear coupling constants between the alpha-alkyl hydrogens and the carbonyl carbons. The experimental 3J values have been compared to theoretical values, and the conformational populations of the alkyl side chains with respect to the trioxopyrimidine ring have been determined. The results show that all these compounds have a very low barrier to rotation for both butyl and ethyl side chains. The barbiturates that do not have a 1'-methyl group in the butyl side chain, butobarbital and amobarbital, have no preferred conformation for either the butyl or ethyl side chains. However, the compounds with a 1'-methyl group, pentobarbital and alpha-methylamobarbital, exhibit preferred conformation for both alkyl chains. The significance of these results to the relationship between conformations and pharmacological activity is discussed.

Barbiturates↗
PubMed1981

Phencyclidine metabolism: resolution, structure, and biological activity of the isomers of the hydroxy metabolite, 4-phenyl-4-(1-piperidinyl)cyclohexanol.

One of the major biotransformation pathways in the metabolism of phencyclidine is hydroxylation at C-4 of the cyclohexane ring to give 4-phenyl-4-(1-piperidinyl)cyclohexanol (1). Since the latter compound can exist as cis and trans isomers and the synthetic mixture has been reported to be biologically active, it was of interest to separate the isomers, test them for biological activity, and determine their ratio as metabolic products of phencyclidine. The synthetic mixture of 1 was separated by TLC and the individual isomers were characterized by 13C and 1H NMR and MS analyses. Preliminary testing of the isomers in the mouse rotarod assay indicates that the trans isomer (1b) is only slightly more active then the cis isomer (1a). Both isomers produced seizure activity and lethality at doses required to produce maximal ataxia.

Animals↗
PubMed1981

Synthesis and pharmacological activity of thiohexital enantiomers.

(S)-(+)- and (R)-(-)-5-Allyl-5-(1-methyl-2-pentynyl)-2-thiobarbituric acid (1, thiohexital) were prepared. The anesthetic activity (loss of righting reflex) and acute toxicity of the optically pure enantiomers of 1 were compared to the racemic isomer in mice. The S(+) isomer was found to be more potent as an anesthetic agent than the R(-) or RS(+/-) isomers. The therapeutic index was 2.5, 2.4, and 3.2 for the RS(+/-), R(-), and S(+) isomers, respectively. There were no significant differences in onset and duration of anesthesia when administered at the respective AD50 values. The prominent side effect is tremor, which is less for the S(+) isomer than for the R(-) or RS(+/-) isomers.

Anesthetics↗
PubMed1980

Positive identification and quantitation of isomeric cocaines by high-performance liquid chromatography.

A high-performance liquid chromatographic procedure for separating and identifying the four isomeric cocaines has been developed. Use of this procedure with an internal standard allows for the determination of the quantity of any isomeric cocaine in an unknown sample. The pitfalls and problems encountered in the use of gas chromatography and mass spectrometry in the analysis of cocaines and ecgonine methyl esters are discussed.

Chromatography, High Pressure Liquid↗
PubMed1980

Synthesis of 2,4-disubstituted 6-methoxy-8-aminoquinoline analogues as potential antiparasitics.

A series of 2,4-disubstituted 8-aminoquinoline analogues were synthesized and evaluated against Plasmodium berghei in mice and Leishmania donovani in hamsters. 8-[[6-(Diethylamino)hexyl]amino]-2-ethyl-6-methoxy-4-methylquinoline (8a) possessed significant activity against L. donovani. 2-Ethyl-4-methylprimaquine (7a) was evaluated against Plasmodium cynomolgi in rhesus monkey and found to have activity equal to that of primaquine.

Aminoquinolines↗