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D R Curtis

Publications and source records attributed to D R Curtis.

At least 19 recordsLinked to original sources
PubMed1991

Novel class of amino acid antagonists at non-N-methyl-D-aspartic acid excitatory amino acid receptors. Synthesis, in vitro and in vivo pharmacology, and neuroprotection.

The isoxazole amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) (1), which is a highly selective agonist at the AMPA subtype of excitatory amino acid (EAA) receptors, has been used as a lead for the development of two novel EAA receptor antagonists. One of the compounds, 2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionic acid (AMOA, 7), was synthesized via O-alkylation by ethyl chloroacetate of the amino acid protected AMPA derivative 4. The other compound, 2-amino-3-[2-(3-hydroxy-5-methylisoxazol-4-yl)-methyl-5-methyl-3-+ ++oxoisoxazolin -4-yl]propionic acid (AMNH, 14) was synthesized with use of 4-(chloromethyl)-3-methoxy-5-methylisoxazole (8) as the starting material. The intermediate 4-(chloromethyl)-2-(3-methoxy-5-methylisoxazol-4-yl)methyl-5-me thylisoxazolin- 3-one (11) was converted into the acetamidomalonate (12), which was stepwise deprotected to give 14. Compounds 7 and 14 were stable in aqueous solution at pH values close to physiological pH. Neither 7 nor 14 showed detectable affinities for the receptor, ion channel, or modulatory sites of the N-methyl-D-aspartic acid (NMDA) receptor complex. Quantitative receptor autoradiographic and conventional binding techniques were used to study the affinities of 7 and 14 for non-NMDA receptor sites. Both compounds were inhibitors of the binding of [3H]AMPA (IC50 = 90 and 29 microM, respectively). Compounds 14 and 7 were both very weak inhibitors of the high-affinity binding of radioactive kainic acid [( 3H]KAIN). Compound 14, but not 7, was, however, shown to be an inhibitor of low-affinity [3H]KAIN binding (IC50 = 40 microM) as determined in the presence of 100 mM calcium chloride. In the rat cortical slice preparation, 7 was shown to antagonize excitation induced by 1 with some selectivity, whereas 14 proved to be a rather selective antagonist of KAIN-induced excitation. Both antagonists showed very weak effects on the excitatory effects of NMDA. Compound 7 was a poor antagonist of excitation by quisqualic acid (2), whereas 14 did not affect excitation by this nonselective AMPA receptor agonist. On cat spinal neurones, both 7 and 14 reduced excitations by 1 and KAIN, but, again, the excitatory effects of 2 were much less sensitive. Compound 14 and, in particular, 7 effectively protected rat striatal neurones against the neurotoxic effects of KAIN, whereas the toxic effects of 1 were reduced only by 7. Neither antagonist showed protection against the cell damage caused by intrastriatal injection of the NMDA agonist quinolinic acid.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Synthesis and single cell pharmacology of potential heterocyclic bioisosteres of the excitatory amino acid antagonist glutamic acid diethyl ester.

A series of heterocyclic analogues of glutamic acid diethyl ester (GDEE), an antagonist at central excitatory amino acid receptors, have been synthesized and tested biologically. (RS)-Ethyl alpha-amino-alpha-(3-ethoxyisoxazol-5-yl)acetate (7), (RS)-ethyl 2-amino-3-(3-ethoxy-5-methylisoxazol-4-yl)propionate (16) and closely related analogues were synthesized. Compound 7, a diethyl derivative of the naturally occurring excitatory amino acid ibotenic acid (IBO), was synthesized from 3-hydroxy-5-methylisoxazole (1) via 3-ethoxyisoxazol-5-ylacetic acid (5) and its ethyl ester. Nitrosation of this ester followed by catalytic reduction gave 7. The ethyl ester of IBO, 9, was synthesized in a similar manner from 3-benzyloxyisoxazol-5-ylacetic acid (8). Ethyl derivatives of the synthetic excitatory amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) were synthesized from 3-hydroxy-4,5-dimethylisoxazole (10) through a diethyl acetylaminomalonate derivative, which upon deprotection gave the 3-ethoxy derivative of AMPA (15). Esterification of 15 gave the diethyl derivative 16 and the ethyl ester of AMPA (18) as well as N-ethylated derivatives of AMPA, 21 and 22 were synthesized. The final products were tested microelectrophoretically. The derivatives 7, 9, 15, 16 and 18 were weak and non-selective excitatory amino acid antagonists, whereas 21 and 22 were found to be inactive.

Action Potentials↗
PubMed1989

Excitatory amino acid agonists. Enzymic resolution, X-ray structure, and enantioselective activities of (R)- and (S)-bromohomoibotenic acid.

The enantiomers of alpha-amino-4-bromo-3-hydroxy-5-isoxazolepropionic acid (4-bromohomoibotenic acid, Br-HIBO, 1) a selective and potent agonist at one class of the central (S)-glutamic acid receptors, were prepared with an enantiomeric excess higher than 98.8% via stereoselective enzymic hydrolysis of (RS)-alpha-(acetylamino)-4-bromo-3-methoxy-5-isoxazolepropionic acid (4) using immobilized aminoacylase. The absolute configuration of the enantiomers of Br-HIBO was established by X-ray crystallographic analysis, which confirmed the expected preference of the enzyme for the S form of the substrate 4. (S)- and (RS)-Br-HIBO were potent neuroexcitants on cat spinal neurones in vivo, while (R)-Br-HIBO was a very weak excitant. Correspondingly, the S enantiomer of Br-HIBO (IC50 = 0.34 microM) was considerably more potent than the R form (IC50 = 32 microM) as an inhibitor of [3H]-(RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([ 3H]AMPA) binding to rat brain synaptic membranes in vitro. In contrast, (S)- and (R)-Br-HIBO were approximately equipotent (IC50 values of 0.22 and 0.15 microM, respectively) as inhibitors of [3H]-(S)-glutamic acid binding in the presence of CaCl2. The enantiomers of Br-HIBO showed no significant affinity for those binding sites on rat brain membranes which are labeled by [3H]kainic acid or [3H]-(R)-aspartic acid.

Animals↗
PubMed1979

A method for continuously monitoring the electrical threshold of single intraspinal nerve fibers.

A method is described for the determination and continuous monitoring of the electrical threshold of single primary afferent fibres within the spinal cord of the cat. The centre barrels of multibarrel micropipettes, filled with 3.6 M NaCl, were used as stimulating electrodes, impulses in single afferents were recorded peripherally and a firing index of 50% was maintained by using a feedback circuit to regulate the amplitude of the stimulating pulses (0.2-0.3 msec duration, less than 2 microA).

Animals↗
PubMed1979

Kainate neurotoxicity and glutamate inactivation.

Dihydrokainate, an inhibitor of high affinity L-glutamate as an excitant of cat spinal neurones in vivo. This action of dihydrokainate was selective in that the effects of excitants taken up actively in vitro by CNS tissue (L-aspartate, D- and L-glutamate and L-homocysteate) were enhanced whereas those of other substances not taken up (acetylcholine, D-homocysteate, kainate and N-methyl-D-aspartate) were not. Since kainate and dihydrokainate have similar potencies as inhibitors of L-glutamate uptake, interference with the inactivation of synaptically released L-glutamate may contribute to the neurotoxic effects of kainate.

Amino Acids↗
PubMed1979

The excitation and depression of spinal neurones by ibotenic acid.

1. The firing of spinal interneurones and Renshaw cells by microelectrophoretic (+/-)-ibotenate, which was approximately eight times more active as an excitant than L-glutamate, was followed by prolonged depression of the sensitivity of the neurones to excitant amino acids and acetylcholine. 2. The depression, which lasted for 15--30 min when ibotenate was ejected for 3--6 min, was blocked by the GABA-antagonist bicuculline methochloride, and was independent of prior firing since it occurred with subthreshold concentrations of ibotenate and when ibotenate firing had been blocked by DL-alpha-aminoadipate. 3. When administered electrophoretically for 5 min, muscimol, a potent GABA agonist, reduced neuronal excitability for prolonged periods and this effect was also prevented by bicuculline methochloride. 4. The depression of neuronal excitability produced by GABA, taurine, isoguvacine or 3-aminopropane sulphonate, ejected for periods of 5--6 min, recovered rapidly. 5. It is suggested that ibotenate is converted in vivo to muscimol or a related compound which has a prolonged, bicuculline-sensitive depressant action on the excitability of neurones.

Action Potentials↗
PubMed1979

Electrical interaction between motoneurons and afferent terminals in cat spinal cord.

1. The electrical threshold of the terminations of single group Ia and II afferent fibers was transiently reduced by the antidromic discharge of the initial segment of spinal motoneurons in the cat. 2. This depolarization of the terminals of afferent fibers known to synapse on motoneurons confirms previous observations of antidromic electrical interaction between these structures.

Animals↗
PubMed1977

Effects of the Areca nut constituents arecaidine and guvacine on the action of GABA in the cat central nervous system.

Arecaidine and guvacine, constituents of the nut of Areca catechu, inhibited the uptake of GABA and beta-alanine, but not that of glycine, by slices of cat spinal cord. In cats anesthetised with pentobarbitone, electrophoretic arecaidine enhanced the inhibitory actions of GABA and beta-alanine, but not those of glycine or taurine, on the firing of spinal neurones. Similarly, electrophoretic guvacine enhanced the inhibition of spinal neurones by GABA but not that by glycine. The uptake of GABA by slices of cat cerebellum was inhibited by arecaidine, and the effect of electrophoretic GABA on the firing of cerebellar Purkinje cells was enhanced by electrophoretic arecaidine. When administered intravenously arecaidine failed to affect synaptic inhibitions considered to be mediated by GABA. Intravenous arecaidine had no effect on either spinal prolonged (presynaptic) inhibition (20mg/kg), dorsal root potentials (20mg/kg) or basket cell inhibition of Purkinje cells (250 mg/kg), although topical arecaidine (6.6-10 x 10(-3) M) blocked this latter inhibition. Large doses of arecaidine (1 g/kg subcutaneous) marginally reduced the lethal effects of bicuculline in mice but appeared to have little or no anticonvulsant activity.

Action Potentials↗
PubMed1977

A pharmacological study of the inhibition of ventral group Ia-excited spinal interneurones.

In cats anaesthetized with pentobarbitone a pharmacological investigation was made of the inhibition by volleys in afferent fibres and ventral roots of physiologically identified Ia interneurones in the ventral horn. The recurrent inhibition of Ia interneurones by Renshaw cells, and the "mutual" inhibition between Ia interneurones, were suppressed by electrophoretic strychnine and are presumably mediated by glycine. Short latency and duration inhibitions by impulses in muscle and cutaneous afferents were also suppressed by strychnine. Electrophoretic GABA inhibited the firing of Ia interneurones and the effects of bicuculline methochloride suggested that this amino acid mediates longer latency and duration inhibition produced by afferent impulses of muscle and cutaneous origin.

Action Potentials↗