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Biomedical subjects

D R Curtis

Publications and source records attributed to D R Curtis.

At least 37 records · Page 2Linked to original sources
PubMed1987

Phaclofen: a peripheral and central baclofen antagonist.

Phaclofen, the phosphonic acid derivative of baclofen, reversibly antagonized the depression of the cholinergic twitch response of the guinea pig ileum and distal colon by either baclofen or GABA. When administered microelectrophoretically, phaclofen reversibly blocked the presumed presynaptic reduction by baclofen of the monosynaptic excitation of spinal interneurones by impulses in primary afferent fibres of the cat but did not block the postsynaptic depressant action of baclofen on these neurones. Phaclofen may thus be useful in determining the physiological significance of central and peripheral bicuculline-insensitive receptors with which GABA and (-)-baclofen interact.

Animals↗
PubMed1987

Ouabain and the membrane transport of amino acids and amines.

Evidence is discussed that ouabain has a direct inhibiting effect on the sodium-dependent uptake of amino acids and amines from the extracellular space of the mammalian central nervous system rather than the inhibition being a consequence of raised intracellular sodium levels.

Amines↗
PubMed1987

Synthesis and biological activity of a GABAA agonist which has no effect on benzodiazepine binding and of structurally related glycine antagonists.

3-Isoxazolols substituted in the 5-position by pyrrolidinyl or piperidyl (referred to, respectively, as PYOLs and PIOLs; see Figure 2 for structures) were designed and synthesized as analogues of the potent and specific GABAA agonist THIP. Activity in the series was markedly dependent upon positional isomerism in the structures. Isomers in which the pyrrolidine or piperidine rings were attached via their 2-positions (2-PYOL and 2-PIOL) had no effect on GABAA receptors in vivo or in vitro. An isomer wherein attachment was via the 4-position (4-PIOL) was a GABAA agonist, but it was unique in not affecting the binding of diazepam in vitro; its 'ring-opened' analogue, (RS)-5-(1-methyl-3-aminopropyl)-3-isoxazolol (11) did not bind significantly to GABAA receptor sites in vitro. In contrast, the 3-positional isomer (3-PIOL) antagonized the inhibitory action of glycine on cat spinal neurons. A similar effect was earlier demonstrated for 3-PYOL. However, in contrast to 3-PYOL, which is approximately equipotent as an antagonist of glycine and GABA, 3-PIOL only marginally reduced the inhibitory effect of GABA. The R and S forms of 3-PIOL, synthesized from the respective isomers of piperidine-3-carboxylic acid with known absolute stereochemistry, had pharmacological profiles indistinguishable from that of racemic 3-PIOL.

Animals↗
PubMed1986

A pharmacological study of group I muscle afferent terminals and synaptic excitation in the intermediate nucleus and Clarke's column of the cat spinal cord.

When administered microelectrophoretically GABA and piperidine-4-sulphonic acid depolarized the central terminations of muscle group Ia and Ib afferent fibres in the lumbar intermediate nucleus and Clarke's column of cats anaesthetised with pentobarbitone sodium. Both this depolarization, and primary afferent depolarization, generated by impulses in other primary afferent fibres which produce prolonged bicuculline-sensitive inhibition of the firing of group I afferent fibre-excited interneurones in the intermediate nucleus and cells in Clarke's column, are reduced by microelectrophoretic bicuculline methochloride. Systemically administered (+/-)-baclofen hydrochloride (maximum dose 8 mg kg-1) depressed the monosynaptic excitation of Clarke's column neurones by impulses in muscle and cutaneous afferent fibres. Microelectrophoretically administered (-)-baclofen reduced the bicuculline-sensitive primary afferent depolarization of group I terminations without, however, reducing the depolarizing action of GABA or piperidine-4-sulphonic acid. The depression by (-)-baclofen of the group I monosynaptic excitation of intermediate nucleus neurones is not reduced by concentrations of bicuculline methochloride adequate to suppress prolonged inhibition of these neurones.

Animals↗
PubMed1986

On the probable absence of GABA receptors on the terminations of motor axon collaterals in the cat spinal cord.

When administered microelectrophoretically, GABA and the GABA-mimetic piperidine-4-sulphonic acid (P4S) appear to have no direct hyperpolarizing or depolarizing effect on the terminations of motor axon collaterals excited electrically in the ventral horn of the lumbar spinal cord of the cat. This lack of effect on axon terminals of motoneurones, which contrasts with the bicuculline-sensitive depolarization by P4S of the spinal terminals of primary afferent fibres, is consistent with previous reports of the probable absence of pharmacologically detectable GABA receptors on the spinal terminals of other central excitatory neurones, namely those of the red and lateral vestibular nuclei.

Animals↗
PubMed1986

Glycine antagonists. Synthesis, structure, and biological effects of some bicyclic 5-isoxazolol zwitterions.

The bicyclic 5-isoxazolol zwitterions 4,5,6,7-tetrahydroisoxazolo[4,3-c] pyridin-3-ol (3, iso-THPO), 5,6,7,8-tetrahydro-4H-isoxazolo [4,3-c]azepin-3-ol (12, iso-THAO), and 5,6,7,8-tetrahydro-4H-isoxazolo [3,4-c]azepin-3-ol (13, iso-THIA), which are structurally related to the glycine antagonist 5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-3-ol (iso-THAZ), have been synthesized and tested biologically. All of these compounds were glycine antagonists approximately equipotent with iso-THAZ during microelectrophoretic ejection near cat spinal neurons. In contrast to iso-THAZ, which also interacts with 4-aminobutyric acid (GABA) receptors in rat brains, neither 12 nor 13 show any significant affinities for GABA binding or uptake mechanisms in vitro. The glycine antagonist 3 was, however, shown also to be a moderately potent inhibitor of GABA uptake. The structure of 12 was established by an X-ray analysis. The bond lengths of the 5-isoxazolol anionic moiety of 12 are in agreement with a pronounced delocalization of the negative charge of this compound.

Animals↗
PubMed1986

Ibotenic acid analogues. Synthesis and biological testing of two bicyclic 3-isoxazolol amino acids.

The bicyclic 3-isoxazolol amino acids (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-4-carboxylic acid (5, 4-HPCA) and (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-6-carboxylic acid (11, 6-HPCA) were synthesized as model compounds for studies of the structural requirements of central excitatory amino acid neurotransmitter receptors. 4-HPCA was synthesized via introduction of a methoxycarbonyl group into the 4-position of the lithiated N-nitroso intermediate 1. The key reaction in the synthesis of 6-HPCA is an intramolecular N-alkylation of the appropriately substituted acetamidomalonate derivative 7 using sodium hydride as a base. On the basis of the pKA values for 4-HPCA the existence of an intramolecular hydrogen bond in the zwitterionic form of this amino acid is proposed. 6-HPCA was shown by 1H NMR spectroscopy to adopt preferentially a conformation with the carboxylate group in an equatorial position. 4- and 6-HPCA were tested as agonists and antagonists at excitatory amino acid receptors on neurones in the cat spinal cord using microelectrophoretic techniques. Neither compound showed significant effects at these receptors.

Action Potentials↗
PubMed1985

Glycine antagonism by RU 5135.

In the spinal cord of the pentobarbitone-anaesthetised cat, microelectrophoretic RU 5135, a steroid derivative, was a potent strychnine-like glycine antagonist, having less effect on the inhibition by GABA of neuronal firing.

Action Potentials↗
PubMed1985

Securinine alkaloids: a new class of GABA receptor antagonist.

Experiments were undertaken to determine the site of action of securinine and related convulsant indolizidines. All of these compounds induced tonic seizures in mice, with CD50 values ranging from 11 to 87 mg/kg. The CD50 for bicuculline was found to be 8 mg/kg. Equilibrium binding assays revealed that securinine and dihydrosecurinine inhibit [3H]GABA binding to rat brain membranes with an IC50 of approximately 50 microM, which is some 7 times less potent than bicuculline. Allosecurinine and virosecurinine have IC50 values greater than 1 mM. Both dihydrosecurinine and securinine inhibited GABA-stimulated benzodiazepine binding in rat brain membranes, though they were somewhat weaker than bicuculline in this respect. Other binding assays revealed that securinine and its analogs were inactive as inhibitors of bicuculline-insensitive GABA binding, benzodiazepine, cholinergic muscarinic, and beta-adrenergic receptor binding. In addition, while thiocyanate ion increased the apparent binding potency of bicuculline 10-fold, it had little effect on that of securinine. Extracellular electrophysiological studies on neurons in the cat spinal cord indicated that securinine and dihydrosecurinine blocked the inhibitory action of GABA while having no effect on that of glycine. Allo- and virosecurinine were much less active as GABA receptor antagonists in this test. These results suggest that, like bicuculline, securinine and dihydrosecurinine are selective antagonists of GABA recognition sites on mammalian central neurons.

Alkaloids↗
PubMed1985

The differential effects of baclofen on segmental and descending excitation of spinal interneurones in the cat.

Intravenous baclofen (1-6.25 mg kg-1) substantially reduced the monosynaptic excitation of neurones in the intermediate nucleus of the cat spinal cord by impulses in group I extensor muscle primary afferent fibres, but had little or no effect on excitation by stimulating fibres of the ipsilateral dorsolateral funiculus or the contralateral red nucleus. Relatively low concentrations of baclofen thus appear not to influence the release of excitatory transmitter from the terminals of rubrospinal, corticospinal and long descending propriospinal fibres, in contrast to the reduction of the release of primary afferent transmitters.

Animals↗
PubMed1985

GABA agonists. Resolution, absolute stereochemistry, and enantioselectivity of (S)-(+)- and (R)-(-)-dihydromuscimol.

(RS)-5-(Aminomethyl)-2-isoxazolin-3-ol (dihydromuscimol, DHM) is a potent 4-aminobutyric acid (GABA) agonist, the inhibitory effects of which on neurons are sensitive to the antagonist bicuculline methochloride (BMC), and it also interacts with the GABA uptake system in vitro. (S)-(+)-DHM (4) and (R)-(-)-DHM (5) were obtained in optically pure forms via resolution of tert-butyloxycarbonyl-protected DHM (1) using cinchonidine as the only resolving agent. The optical purity and absolute stereochemistry of 4 and 5 were established by chemical correlation to the (S)-(+) enantiomer of 3-hydroxy-4-aminobutyric acid (GABOB). While 4 was a specific and potent BMC-sensitive GABA agonist in vivo and in vitro, possibly the most potent GABA agonist so far described, the inhibition of GABA uptake by DHM proved to reside exclusively in the (R)-(-) enantiomer (5). The affinity of 5 for BMC-sensitive GABA receptor sites in vitro was some 50 times lower than that of 4. Compounds 4 and 5 can be considered semirigid isosteres of the conformationally flexible GABA analogues (S)-(+)- and (R)-(-)-GABOB, respectively, which show a very low degree of enantioselectivity with respect to GABA synaptic mechanisms. This correlation between the degree of enantioselectivity and conformational mobility of chiral GABA analogues might be of importance for the design of new drugs with specific actions at synapses at which GABA is the transmitter.

Animals↗
PubMed1985

Synthesis and structure-activity studies on excitatory amino acids structurally related to ibotenic acid.

With use of ibotenic acid as a lead, analogues of (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and of (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA) were synthesized and tested as excitants of neurons in the cat spinal cord by using microelectrophoretic techniques and as inhibitors of the binding of kainic acid in vitro. Like AMPA and 7-HPCA, (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridine-5-carboxylic acid (10, 5-HPCA) and (RS)-3-hydroxy-5-(bromomethyl)isoxazole-4-propionic acid (11, ABPA) proved to interact potently and selectively with central quisqualic acid receptors, assumed to represent physiological glutamic acid receptors. Analogues of 7-HPCA or 10, in which one or both of the acid groups were masked, were very weak or inactive as neuronal excitants and had no antagonistic effects at excitatory amino acid receptors. The structure of 7-HPCA in the crystalline state was established by X-ray analyses. The preferred conformation of 10 in aqueous solution was determined by 1H NMR spectroscopy. On the basis of these studies, 7-HPCA as well as 10 were shown to adopt preferentially conformations with the carboxylate groups in equatorial positions. It is suggested that AMPA, 7-HPCA, and 10 interact with quisqualic acid receptors in conformations essentially reflecting active conformation(s) of glutamic acid at these receptors.

Amino Acids↗
PubMed1985

GABA-mimetic activity and effects on diazepam binding of aminosulphonic acids structurally related to piperidine-4-sulphonic acid.

The relationship between structure, in vivo activity, and in vitro activity of some analogues of the gamma-aminobutyric acid (GABA) agonist piperidine-4-sulphonic acid (P4S) was studied. The syntheses of 1,2,3,6-tetrahydropyridine-4-sulphonic acid (DH-P4S) and (RS)-pyrrolidin-3-yl-methanesulphonamide (PMSA-amide) are described. Like P4S, its unsaturated analogue DH-P4S and the five-ring isomer (RS)-pyrrolidin-3-yl-methanesulphonic acid (PMSA) were bicuculline methochloride (BMC)-sensitive inhibitors of the firing of neurones in the cat spinal cord. Whereas isonipecotic acid was less potent than its unsaturated analogue isoguvacine as a GABA-mimetic and as an inhibitor of GABA binding, the opposite relative potencies of P4S and DH-P4S were observed, P4S being proportionally more potent than DH-P4S. In contrast with P4S and DH-P4S, PMSA, which is an analogue of the potent GABA uptake inhibitor and BMC-sensitive GABA-mimetic homo-beta-proline, was a relatively weak inhibitor of GABA uptake in vitro. PMSA-amide was more than two orders of magnitude weaker than PMSA as an inhibitor of GABA binding and did not significantly affect GABA uptake in vitro. The effects of 3-aminopropanesulphonic acid (3-APS), PMSA, P4S, and DH-P4S on the binding of [3H]diazepam in vitro at 30 degrees C, in the presence or absence of chloride ions, were studied and compared with those of the structurally related amino acids GABA, homo-beta-proline, isonipecotic acid, and isoguvacine. Under these conditions the aminosulphonic acids were weaker than the respective amino acids in enhancing [3H]diazepam binding, the difference being more pronounced in the absence of chloride.

Animals↗
PubMed1985

A neurophysiological analysis of the effect of kainic acid on nerve fibres and terminals in the cat spinal cord.

Kainic acid was administered micro-electrophoretically in relatively small amounts (approx. 0.15 nmol) near gastrocnemius motoneurones in the spinal cord of cats anaesthetized with sodium pentobarbitone. After initial excitation, extracellularly recorded orthodromic and antidromic field potentials were reduced. Such neurophysiological evidence for motoneuronal damage or death persisted for 5 h, the longest period of observation. At the site of administration, the terminations of gastrocnemius group Ia afferent fibres were electrically inexcitable for approximately 1 h. Subsequently, the number and excitability of these terminations appeared to be normal, as were the depolarizing actions at bicuculline-sensitive receptors of micro-electrophoretic piperidine-4-sulphonic acid and of gamma-aminobutyric acid (GABA) released at axoaxonic synapses on these terminations. Central myelinated and non-myelinated fibres and terminals of muscle group Ia afferent fibres, and the synaptic release of GABA on these terminals at axo-axonic synapses formed by certain spinal interneurones, thus appear to be relatively insensitive to kainic acid administered in amounts which damage or destroy motoneurones.

Action Potentials↗
PubMed1984

The effect of GABA on lumbar terminations of rubrospinal neurons in the cat spinal cord.

Although GABA and piperidine-4-sulphonic acid depolarize I a afferent terminations in the cat spinal cord by activation of bicuculline-sensitive GABA receptors, no evidence was obtained for a bicuculline-sensitive alteration by either gabamimetic of the electrical threshold of rubrospinal terminations in the spinal intermediate nucleus. The terminal axonal arborizations in the spinal cord of neurons in the red nucleus thus do not have GABA receptors similar to those on the cell bodies. The results are discussed in relation to the depolarizing action of GABA on some central neurons, and on neurons with peripheral cell bodies, and to probable differences in the intracellular chloride content of neurons having peripheral or central cell bodies, and thus of different embryological origin. A presynaptic depolarizing inhibitory process mediated by GABA appears to be confined to the terminals of primary afferent fibres in the mammalian central nervous system.

Afferent Pathways↗
PubMed1984

The effects of naloxone, morphine and methionine enkephalinamide on Ia afferent terminations in the cat spinal cord.

Naloxone, morphine, Met5-enkephalinamide (MENKA) and procaine were administered microelectrophoretically near extracellularly stimulated extensor muscle group Ia afferent fibres and terminations in the lumbar spinal cord of cats anaesthetized with pentobarbitone sodium. Observations were made of effects on the electrical threshold, on the depolarizing action of GABA or piperidine-4-sulphonate (P4S), and on bicuculline-sensitive primary afferent depolarization (PAD) generated by tetanic stimulation of flexor muscle low threshold afferents. All 4 agents reversibly elevated the threshold of Ia fibres in the dorsal column and Ia terminations in the ventral horn. The depolarizations of terminations by GABA or P4S were also reduced, an effect, which for all except MENKA, probably accounted for a concomitant reduction in PAD. In the absence of a consistent effect on either threshold or depolarization by GABAmimetics, MENKA reversibly diminished PAD, an action blocked by naloxone. Intravenously administered naloxone, in doses known to enhance spinal monosynaptic excitation in the cat, had no effect on GABAergic PAD and little or no effect on Ia termination threshold. The results are discussed in relation to a naloxone-sensitive effect of MENKA which reduces transmitter release from GABAergic axo-axonic synapses on Ia terminals, but which does not account for the enhancement of spinal reflexes by naloxone.

Afferent Pathways↗