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Biomedical subjects

R G Booth

Publications and source records attributed to R G Booth.

At least 37 records · Page 2Linked to original sources
PubMed1990

Presynaptic inhibition of dopamine synthesis in rat striatal tissue by enantiomeric mono- and dihydroxyaporphines.

Presynaptic autoreceptor-mediated modulation of dopamine (DA) synthesis was evaluated as the inhibition of tyrosine hydroxylase activity by enantiomeric mono- and dihydroxyaporphines with minced striatal tissue from rat brain. The isomers of N-n-propylnorapomorphine (NPA) both inhibited tyrosine hydroxylase activity [IC50 = 0.3 and 1.0 microM for (R)-(-)- and (S)-(+)-NPA, respectively; R/S potency = 3.6]. Their effects were fully blocked by the nonselective DA receptor antagonist fluphenazine, as well as by the D2-selective antagonist spiperone, but not by the D1 antagonist SCH-23390. These results suggest a D2-type autoreceptor-mediated inhibition of DA synthesis, with limited enantiomeric selectivity of this catechol-aporphine. The corresponding monohydroxy analogs, (R)-(-)- and (S)-(+)-11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) were about 100 times less potent (IC50 = 42 and 87 microM, respectively) than the NPA isomers in fully inhibiting the enzyme activity in normal tissue but, after depletion of endogenous DA by acute in vivo pretreatment with reserpine (which did not alter the number of D1 or D2 specific binding sites), (R)-(-)-11-OH-NPa was a highly potent but partial agonist (IC25 = 7 nM). Fluphenazine and spiperone fully antagonized the inhibition of tyrosine hydroxylase by (R)-(-)-11-OH-NPa in reserpinized tissue, but SCH-23390 was ineffective. Actions mediated by endogenous DA probably contribute to the effect of high concentrations of (R)-(-)-11-Oh-NPa to evoke a full inhibition of DA synthesis, but its high potency partial agonist effects appear to be mediated by D2-autoreceptors. (S)-(+)-11-OH-NPa was a very weak partial agonist in reserpinized tissue, with an IC25 = 30 microM (essentially the same as normal tissue); thus, (R)-(-)-11-OH-NPa was greater than 4,000 times more potent than its S-(+)-enantiomer in the absence of endogenous DA. These results demonstrate that NPA, which contains a catechol moiety, acts as a full agonist to inhibit striatal DA synthesis via a presynaptic autoreceptor of the D2 type, with only slight stereoselectivity, and that its monohydroxy analog is a very potent but partial D2 autoreceptor agonist, with very high stereoselectivity.

Animals↗
PubMed1989

1-methyl-4-phenylpyridinium (MPP+) analogs: in vivo neurotoxicity and inhibition of striatal synaptosomal dopamine uptake.

The ability of various 1-methyl-4-phenylpyridinium (MPP+) analogs to inhibit the uptake of tritium labeled dopamine and MPP+ by synaptosomes prepared from neostriata of male C57 Black mice was measured and compared with their dopaminergic neurotoxic potential which was estimated by an in vivo intracerebral microdialysis technique. The correlation observed between these two properties suggests that nerve terminal uptake is an important step in the expression of the nigrostriatal toxicity of structural analogs of MPP+. The uptake inhibition and neurotoxic properties of this series of compounds appear to be highly structurally sensitive and suggest that few nitrogenous bases will be potent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-type neurotoxins.

1-Methyl-4-phenylpyridinium↗
PubMed1989

Intracerebral microdialysis neurotoxicity studies of quinoline and isoquinoline derivatives related to MPTP/MPP+.

The in vivo dopaminergic neurotoxicity of a series of quinoline and isoquinoline derivatives was assessed in rats using an intrastriatal microdialysis technique that measures the release of dopamine. The N-methyl quaternary salts of these two heterocyclic aromatic systems displayed about 10% of the potency of MPP+ in this assay. Furthermore, tetrahydroisoquinoline, which has been reported to be present in human brain, and N-methyltetrahydroisoquinoline were found to be MAO-B substrates, being oxidized at about 3% the rate of MPTP. Thus, although tetrahydroisoquinoline and N-methyltetrahydroisoquinoline are not neurotoxic, it is conceivable that the chronic endogenous formation of quaternary species could cause neuronal lesions that contribute to the etiology of idiopathic Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Studies on semirigid tricyclic analogues of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

The tetrahydro-beta-carboline derived from the condensation of N-methyltryptamine and formaldehyde, a semirigid tricyclic analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) tha has been detected in the brains of normal laboratory rats, is biotransformed in a monoamine oxidase B (MAO-B) catalyzed reaction to the corresponding dihydro compound at a rate that is approximately 0.5% of that observed with MPTP. The corresponding tetrahydroindenopyridine in which the double bond beta,gamma to the nitrogen atom retains allylic character is a somewhat better MAO-B substrate. The steric bulk of the nitrogen and methylene bridges in addition to ring strain present in the proposed carbon-centered radical intermediates derived from these types of tricyclic structures may contribute to their relatively poor MAO-B substrate properties. Although no MPTP-like neurotoxic properties were observed following acute administration of the test compounds to mice, we speculate that the chronic accumulation of beta-carbolinium type metabolites could contribute to the rate of nigrostriatal cell loss associated with idiopathic Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

In vivo dopaminergic neurotoxicity of the 2-beta-methylcarbolinium ion, a potential endogenous MPP+ analog.

The MPP+-like neurotoxicity of the 2-methyl-beta-carbolinium species, a possible endogenous condensation product structurally related to MPP+, has been assessed by an intracerebral microdialysis technique. Although much less potent, this compound appears to cause the selective and irreversible destruction of nigrostriatal nerve terminals in rat brain in a manner similar to that observed under comparable conditions with MPP+.

1-Methyl-4-phenylpyridinium↗
PubMed1988

Selective inhibition of Leishmania dihydrofolate reductase and Leishmania growth by 5-benzyl-2,4-diaminopyrimidines.

The classical anti-microbial antifolates trimethoprim, pyrimethamine, and cycloguanil are poor inhibitors of purified dihydrofolate reductase (DHFR) from Leishmania major. They show no selectivity for Leishmania DHFR relative to the human enzyme, and it is not surprising that they are ineffectual as anti-leishmanial agents. Several 5-(substituted-benzyl)-2,4-diaminopyrimidines have been screened as inhibitors for purified L. major and human DHFRs. These compounds inhibit Leishmania DHFR with I50 values ranging from 0.2 to 11 microM, and show about 5 to greater than 100-fold greater selectivity for the parasite DHFR than the human enzyme. These pyrimidine analogs are more potent inhibitors of Leishmania promastigote and amastigote growth than the classical anti-microbial antifolates, and serve as lead compounds for the development of new selective antileishmanial agents.

Animals↗
PubMed1987

Inhibition of NADH oxidation by pyridine derivatives.

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an impurity in an illicit drug, is expressed after its oxidation to 1-methyl-4-phenylpyridinium by monoamine oxidase. The pyridinium is concentrated by carrier-mediated transport into the mitochondria where it inhibits NADH dehydrogenase and, hence, ATP synthesis. Some structurally related compounds have been tested for their effect on the oxidation of NAD+-linked substrates in intact mitochondria, and for the inhibition of the accumulation of the pyridinium into mitochondria and of NADH dehydrogenase activity in a membrane preparation. Some pyridine derivatives are more inhibitory to NADH dehydrogenase than is 1-methyl-4-phenylpyridinium but these are not concentrated into mitochondria by the uptake system. 4-Phenylpyridine, one of the most effective inhibitors, both occurs naturally and is an environmental pollutant.

1-Methyl-4-phenylpyridinium↗
PubMed1987

Quantitative structure-activity relationship of triazine-antifolate inhibition of Leishmania dihydrofolate reductase and cell growth.

Quantitative structure-activity relationships have been formulated for the inhibition of Leishmania major dihydrofolate reductase (DHFR) and for inhibition of promastigote cell growth by a series of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-substituted-phenyl)-s-triazine s. The inhibition of DHFR is best correlated by a modified variable for hydrophobicity of the 3-X substituent (pi'3), an alkoxy group indicator variable (IOR), a disposable parameter (beta) obtained by iteration, and a variable that parameterizes steric effects (MR) in the equation, log 1/Ki = 0.65 pi'3 - 1.22 log (beta X 10 pi'3 + 1) - 1.12IOR + 0.58MRY + 5.05 (r = 0.965). The EC50 values for triazine inhibition of L. major cell growth in culture are correlated by the equation log 1/EC50 = 0.21 pi 3 + 0.44 log 1/Ki + 0.53 (r = 0.960). When compared to DHFR from human, other vertebrates, and E. coli, L. major DHFR differs in that it optimally binds triazine congeners that are much more hydrophobic. Furthermore, in contrast to other DHFR's studied, triazine binding to L. major DHFR does not seem to be influenced by the electronic characteristics of the 3-X substituent of the parent triazine molecule. However, L. major DHFR is more sensitive to the steric effects and polarizability of the 3-X substituent. Our results indicate that triazines inhibit L. major promastigote growth via direct inhibition of DHFR as is shown by the good correlation between log 1/Ki values for inhibition of the purified enzyme and log 1/EC50 values for inhibition of cell culture growth. Two lipophilic, sterically large analogues of this triazine series showed selectivity for L. major DHFR over human DHFR. Further optimization of the MR and IOR terms in the above QSAR equations may provide even more selective inhibitors.

Folic Acid Antagonists↗
PubMed1981

Development of optical quality in the infant monkey (Macaca nemestrina) eye.

Behavioral measures of the development of spatial vision, such as contrast sensitivity and acuity, do not distinguish between optical and neural contributions to the emergence of adult visual sensitivity in primates. The optical contribution to visual development in monkeys was estimated by measuring retinal image quality in the eyes of seven infant monkeys ranging in age from 2 days to 9 months. Results from both longitudinally and cross-sectionally tested monkeys indicate that the optics in infant monkeys are good at birth but that improvements with age can be found. The optical modulation transfer function shows that contrast transmission through the optics increases with age at all measurable spatial frequencies. Adult levels of optical quality are seen by 13 weeks of age. In comparison to the large improvements found during development in contrast sensitivity in monkeys. the optical changes are small and probably pose no major limit to the development of spatial vision in this species.

Age Factors↗