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J W Daly

Publications and source records attributed to J W Daly.

At least 37 records · Page 2Linked to original sources
PubMed1999

Chronic effects of xanthines on levels of central receptors in mice.

1. Chronic ingestion of caffeine causes a significant increase in levels of A1-adenosine, nicotinic and muscarinic receptors, serotonergic receptors, GABAA receptors and L-type calcium channels in cerebral cortical membranes from mice NIH Swiss strain mice. 2. Chronic theophylline and paraxanthine had effects similar to those of caffeine except that levels of L-type channels were unchanged. Chronic theobromine, a weak adenosine antagonist, and 1-isobutyl-3-methylxanthine (IBMX), a potent adenosine antagonist and phosphodiesterase inhibitor, caused only an increase in levels of A1-adenosine receptors. A combination of chronic caffeine and IBMX had the same effects on receptors as caffeine alone. Chronic 3,7-dimethyl-1-propargylxanthine (DMPX), a somewhat selective A2A-antagonist, caused only an increase in levels of A1-adenosine receptors. Pentoxifylline, an adenosine-uptake inhibitor inactive at adenosine receptors, had no effect on receptor levels or calcium channels. 3. A comparison of plasma and brain levels of xanthines indicated that caffeine penetrated more readily and attained somewhat higher brain levels than theophylline or theobromine. Penetration and levels were even lower for IBMX, paraxanthine, DMPX, and pentoxyfylline. 4. The results suggest that effective blockade of both A1 and A2A-adenosine receptors is necessary for the full spectrum of biochemical changes elicited by chronic ingestion of xanthines, such as caffeine, theophylline, and paraxanthine.

1-Methyl-3-isobutylxanthine↗
PubMed1998

[Is caffeine addictive? The most widely used psychoactive substance in the world affects same parts of the brain as cocaine].

Caffeine is the most widely used psychoactive substance in the world. In Western society, at least 80 per cent of the adult population consumes caffeine in amounts large enough to have an effect on the brain. Is this due to caffeine dependence? The article reviews the abuse potential of caffeine in relation to its mechanisms of action. Caffeine affects the same parts of the brain as cocaine, but in completely different ways. There is evidence for caffeine withdrawal symptoms, and caffeine does act as a weak reinforcer, but neither effect is as pronounced as those associated with cocaine. Nor does caffeine use appear to pose any threat to the individual or to society. There is thus no need to add diagnosis "caffeine dependence" to the psychiatric manuals.

Adult↗
PubMed1998

6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors.

A series of tropane derivatives, related in structure to baogongteng A (1), an alkaloid from a Chinese herb, were synthesized. 6beta-Acetoxynortropane (5) had weak affinity (Ki 22 microM) for central (M1) muscarinic receptors in a [3H]quinuclidinyl benzilate binding assay but had extremely high affinity (Ki 2.6 nM) and selectivity for M2-muscarinic receptors expressed in CHO cells. It had 13-fold lower affinity for M4-receptors, 260-fold lower affinity for M3-receptors, and 8200-fold lower affinity for M1-receptors expressed in CHO cells. The 6beta-carbomethoxy analogue (14) of baogongteng A had only weak affinity for M2-muscarinic receptors, as did 6beta-carbomethoxynortropane (13) and 6beta-acetoxytropane (4). In transfected CHO cells, 6beta-acetoxynortropane (5) was an agonist at M2-receptors, based on a GTP-elicited decrease in affinity, and a full agonist with an IC50 of 11 nM at M4-receptors, based on inhibition of cyclic AMP accumulation, while being a full agonist at M1-receptors with an EC50 of 23 nM and a partial agonist at M3-receptors with an EC50 of 3.6 nM, based in both cases on stimulation of phosphoinositide breakdown. All of the 16 tropane derivatives had weak affinities for central alpha4beta2-nicotinic receptors with 6beta-carbomethoxynortropane (13) having the highest affinity, which was still 150-fold less than that of nicotine. 6beta-Acetoxynortropane (5) represents a potent muscarinic agonist with apparent selectivity toward M2-receptors.

Adenylyl Cyclase Inhibitors↗
PubMed1998

Thirty years of discovering arthropod alkaloids in amphibian skin.

Amphibian skin has provided a wide range of biologically active alkaloids. During the past 30 years, over 400 alkaloids of over 20 structural classes have been detected. These include the batrachotoxins, which are potent and selective activators of sodium channels, the histrionicotoxins, which are potent noncompetitive blockers of nicotinic receptor-gated channels, the pumiliotoxins and related allo- and homo-pumiliotoxins, which have myotonic and cardiotonic activity due to effects on sodium channels, and epibatidine, which has potent antinociceptive activity due to agonist activity at nicotinic receptors. Further classes of alkaloids from amphibian skin include pyrrolidines and piperidines, decahydroquinolines, pyrrolizidines, various indolizidines, quinolizidines, and tricyclic gephyrotoxins, pyrrolizidine oximes, pseudophrynamines, coccinellines, and cyclopentaquinolizidines. Most alkaloids of amphibian skin appear to be sequestered from dietary arthropods. The source of the batrachotoxins, histrionicotoxins, pumiliotoxins, epibatidine, and certain izidines are unknown.

Alkaloids↗
PubMed1997

Loperamide: a positive modulator for store-operated calcium channels?

The depletion of inositol trisphosphate-sensitive intracellular pools of calcium causes activation of store-operated calcium (SOC) channels. Loperamide at 10-30 microM has no effect on intracellular calcium levels alone, but augments calcium levels in cultured cells when SOC channels have been activated. In HL-60 leukemic cells, the apparent positive modulatory effect of loperamide on SOC channels occurs when these channels have been activated after ATP, thapsigargin, or ionomycin-elicited depletion of calcium from intracellular storage sites. Loperamide has no effect when levels of intracellular calcium are elevated through a mechanism not involving SOC channels by using sphingosine. Loperamide caused augmentation of intracellular calcium levels after activation of SOC channels in NIH 3T3 fibroblasts, astrocytoma 1321N cells, smooth muscle DDT-MF2 cells, RBL-2H3 mast cells, and pituitary GH4C1 cells. Only in astrocytoma cells did loperamide cause an elevation in intracellular calcium in the absence of activation of SOC channels. The augmentation of intracellular calcium elicited by loperamide in cultured cells was dependent on extracellular calcium and was somewhat resistant to agents (SKF 96365, miconazole, clotrimazole, nitrendipine, and trifluoperazine) that in the absence of loperamide effectively blocked SOC channels. It appears that loperamide augments influx of calcium through activated SOC channels.

3T3 Cells↗
PubMed1997

Pseudophrynaminol: a potent noncompetitive blocker of nicotinic receptor-channels.

(+/-)-Pseudophrynaminol inhibited carbamylcholine-elicited sodium-22 influx with an IC50 value of about 0.3 microM in both rat pheochromocytoma PC12 cells (ganglionic-type nicotinic receptor) and human medulloblastoma TE671 cells (neuromuscular-type nicotinic receptor). The inhibition in both cell lines appeared to be noncompetitive in nature. In rat cerebral cortical membranes, pseudophrynaminol had only low affinity (Ki 35 microM) for the agonist site on central nicotinic receptors at which [3H]nicotine binds. Pseudophrynaminol, at 10 microM, had marginal effects on a variety of other central receptors, and even at 100 microM inhibited batrachotoxin-elicited sodium-22 influx in a synaptoneurosomal preparation by only 40%. It had no effect at 30 microM on acetylcholinesterase and was a weak inhibitor of butyrylcholinesterase. Thus, pseudophrynaminol appears to be a potent, rather specific, noncompetitive inhibitor of ganglionic and neuromuscular nicotinic receptor-channels.

Adult↗
PubMed1997

Synthesis and nicotinic activity of epiboxidine: an isoxazole analogue of epibatidine.

Synthetic (+/-)-epiboxidine (exo-2-(3-methyl-5-isoxazolyl)-7-azabicyclo[2.2.1]heptane) is a methylisoxazole analog of the alkaloid epibatidine, itself a potent nicotinic receptor agonist with antinociceptive activity. Epiboxidine contains a methylisoxazolyl ring replacing the chloropyridinyl ring of epibatidine. Thus, it is also an analog of another nicotinic receptor agonist, ABT 418 ((S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole), in which the pyridinyl ring of nicotine has been replaced by the methylisoxazolyl ring. Epiboxidine was about 10-fold less potent than epibatidine and about 17-fold more potent than ABT 418 in inhibiting [3H]nicotine binding to alpha 4 beta 2 nicotinic receptors in rat cerebral cortical membranes. In cultured cells with functional ion flux assays, epiboxidine was nearly equipotent to epibatidine and 200-fold more potent than ABT 418 at alpha 3 beta 4(5) nicotinic receptors in PC12 cells. Epiboxidine was about 5-fold less potent than epibatidine and about 30-fold more potent than ABT 418 in TE671 cells with alpha 1 beta 1 gamma delta nicotinic receptors. In a hot-plate antinociceptive assay with mice, epiboxidine was about 10-fold less potent than epibatidine. However, epiboxidine was also much less toxic than epibatidine in mice.

Animals↗
PubMed1997

Absence of tetrodotoxins in a captive-raised riparian frog, Atelopus varius.

Bufonid frogs of the genus Atelopus contain two classes of skin toxins, namely the steroidal bufadienolides and the water-soluble tetrodotoxins. Frogs of the Panamanian species Atelopus varius have now been raised in captivity and levels in skin extracts of bufadienolides and of tetrodotoxin-like compounds assessed, using inhibition of [3H]ouabain binding and inhibition of [3H]saxitoxin binding, respectively. Levels of ouabain equivalents, corresponding to bufadienolides, were comparable to those found in wild-caught frogs from the same population in Panama, while tetrodotoxin-like activity was undetectable. The results strongly implicate environmental factors, perhaps symbiotic microorganisms, in the genesis of tetrodotoxins in the skin of frogs of the genus Atelopus, while indicating that the frog itself produces the skin bufadienolides.

Amphibian Venoms↗
PubMed1997

Absence of skin alkaloids in captive-raised Madagascan mantelline frogs (Mantella) and sequestration of dietary alkaloids.

Mantelline frogs of the genus Mantella contain a variety of pumiliotoxin, allopumiliotoxin and homopumiliotoxin alkaloids in their skin. Pyrrolizidines, indolizidines and quinolizidines are also present. In contrast, captive-raised frogs (Mantella aurantiaca) have no alkaloids detectable in skin extracts. Frogs fed alkaloid-dusted fruit flies accumulate alkaloids into their skin. Thus, these mantelline frogs, like the neotropical dendrobatid frogs, appear dependent on dietary sources for their skin alkaloids and have the requisite alkaloid-sequestering system(s).

Alkaloids↗
PubMed1997

Alkaloid 223A: the first trisubstituted indolizidine from dendrobatid frogs.

The structure of alkaloid 223A (1), the first member of a new class of amphibian alkaloids, purified by HPLC from a skin extract of a Panamanian population of the frog Dendrobates pumilio Schmidt (Dendrobatidae) has been established as (5R,6S,8R,9S)- or (5S,6R,8S,9R)-6,8-diethyl-5-propylindolizidine, based on GC-MS, GC-FTIR, and 1H-NMR spectral studies. Three higher homologs of 223A, namely alkaloids 237L (2), 251M (3), and 267J (4), have been detected in other extracts, and tentative structures are proposed.

Animals↗
PubMed1997

Ibogaine: a potent noncompetitive blocker of ganglionic/neuronal nicotinic receptors.

Ibogaine noncompetitively blocked (IC50 approximately 20 nM) 22NaCl influx through ganglionic-type nicotinic receptor channels of rat pheochromocytoma PC12 cells. The major metabolite O-des-methylibogaine was 75-fold less active, and O-t-butyl-O-des-methylibogaine was 20-fold less active. Ibogaine was relatively weak as a blocker (IC50 approximately 2000 nM) of the neuromuscular-type nicotinic receptor channels in human medulloblastoma TE671 cells. The blockade of nicotinic responses by ibogaine was only partially reversible in PC12 cells. In vivo, ibogaine at 10 mg/kg completely blocked epibatidine-elicited antinociception in mice, a response that is mediated by central nicotinic receptor channels. There was no significant blockade of the epibatidine response at 24 hr after the administration of 40 mg/kg ibogaine. The blockade of nicotinic channels could contribute to the antiaddictive properties of ibogaine.

Animals↗
PubMed1996

Spiropyrrolizidines: a new class of blockers of nicotinic receptors.

The spiropyrrolizidine oximes 236 and 222 and a related spiropyrrolizidine alkaloid, nitropolyzonamine, block nicotinic receptor channels in rat pheochromocytoma PC12 cells and in human medulloblastoma TE671 cells. In PC12 cells with an alpha 3 beta 4(5)-nicotinic receptor, both the spiropyrrolizidine oxime 236 and nitropolyzonamine had IC50 values of about 1.5 microM, while spiropyrrolizidine oxime 222 had an IC50 value of 2.6 microM versus carbamylcholine-elicited sodium-22 influx. In TE671 cells with an alpha 1 beta 1 gamma delta nicotinic receptor, the spiropyrrolizidine oximes 236, 222, and nitropolyzonamine had IC50 values of 9.5, 14, and 67 microM, respectively. The inhibitions by the spiropyrrolizidine oxime 236 and nitropolyzonamine appeared to be noncompetitive in nature in both cell lines. In rat cerebral cortical membranes, binding of [3H]nicotine to alpha 4 beta 2 nicotinic receptors was not inhibited significantly by 10 microM concentrations of the spiropyrrolizidine oxime 236, or by nitropolyzonamine, as expected for a noncompetitive blocker. Both compounds at 10 microM had marginal effects on a variety of central receptors, but did inhibit binding of [3H]1,3-di(2-tolyl) guanidine to sigma receptors in mouse brain membranes with IC50 values of about 0.5 microM. The spiropyrrolizidine oxime 236 at 10 microM had no effect on batrachotoxin-elicited sodium influx in guinea pig cerebral cortical synaptoneurosomes or on ATP-elicited calcium influx in PC12 cells. Such spiropyrrolizidines represent a new structural class of blockers of nicotinic receptor channels with selectivity for ganglionic-type receptors.

Animals↗
PubMed1996

Tetrahydrobenzothiophenone derivatives as a novel class of adenosine receptor antagonists.

A novel class of non-nitrogen-containing heterocycles, the tetrahydrobenzothiophenones, was found to bind to adenosine receptors as antagonists in the micromolar range. Affinity was determined in radioligand-binding assays at rat brain A1 and A2a receptors. A structure-activity analysis indicated that a 3-thioether group is favored and affinity at A2a, but not at A1, receptors is highly dependent on this thioether substituent. A carboxylic acid-derived substituent is required at the 1-position of the thiophene ring, with esters being more potent in binding at A1 receptors than the corresponding carboxyl hydrazide or carboxylic acid derivatives. The methyl (15) and ethyl (16) esters are about equipotent at A1 but not at A2a receptors. A 4-keto group on the saturated ring is favored for receptor affinity. Dimethyl substitution at the 6-position of the saturated ring is allowed. One of the most potent derivatives was the nonselective compound ethyl 3-(benzylthio)-4-oxo-4,5,6,7-tetrahydrobenzo[c] thiophene-1-carboxylate (BTH4, 7; Figure 1), which antagonized adenosine agonist-induced inhibition of adenylyl cyclase in rat adipocyte membranes with a KB value of 1.62 +/- 0.73 microM and adenosine agonist-induced stimulation of adenylyl cyclase in pheochromocytoma cell membranes with a KB value of 9.19 +/- 0.98 microM. Displacement of radioligand binding by BTH4 (7) at cloned human A3 receptors was negligible but one slightly A3 selective compound (11, 3.9-fold over A1 and >7.5-fold over A2a) was found. A 1-methylpropyl thioether (17) was 29-fold selective for A1 and A2a receptors. BTH4 (7) alone, at 10 mg/kg, stimulated locomotor activity in mice but paradoxically acted, under certain circumstances, synergistically with an A1 selective agonist to depress locomotor activity. A pharmacophore model relating structural features of xanthine and non-xanthine adenosine antagonists to BTH4 (7) suggests a high degree of similarity in electrostatic surfaces, assuming that the thiophene ring superimposes the region of the uracil ring of xanthines.

Animals↗
PubMed1996

Adenosine receptor ligands: differences with acute versus chronic treatment.

Adenosine receptors have been the target of intense research with respect to potential use of selective ligands in a variety of therapeutic areas. Caffeine and theophylline are adenosine receptor antagonists, and over the past three decades a wide range of selective agonists and antagonists for adenosine receptor subtypes have been developed. A complication to the therapeutic use of adenosine receptor ligands is the observation that the effects of acute administration of a particular ligand can be diametrically opposite to the chronic effects of the same ligand. This 'effect inversion' is discussed here by Ken Jacobson and colleagues, and has been observed for effects on cognitive processes, seizures and ischaemic damage.

Animals↗
PubMed1996

A new secotrinervitane diterpene isolated from soldiers of the Madagascan termite species, Nasutitermes canaliculatus.

Reported herein is the X-ray crystallographic structure of a novel 10-oxygenated secotrinervitane diterpene, 3 alpha, 10 alpha-diacetoxy-7,16-secotrinervita-7,11,15(17)-triene (4), from soldiers of the endemic Madagascan termite Nasutitermes canaliculatus, which was compared with an energy-minimized structure obtained by computer molecular modeling. We also report 1H- and 13C-NMR and MS data for this new diterpene.

Animals↗
PubMed1996

A 1,4-disubstituted quinolizidine from a Madagascan mantelline frog (Mantella).

A major alkaloid, 217A, in skin extracts of a mantelline frog (Mantella baroni) was isolated by HPLC and the structure defined by 1H-NMR spectral analysis as (1R,4S,10S)- or (1R,4R,10R)- 1-methyl-4-(Z)-(1-pent-2-en-4-ynyl) quinolizidine (1). Four other alkaloids-207I (2), 231A (3), 233A (4), and 235E' (5)-detected in frog skin extracts are proposed to be 1,4-disubstituted quinolizidines based on diagnostic mass and FTIR spectra.

Animals↗
PubMed1995

Maitotoxin-elicited calcium influx in cultured cells. Effect of calcium-channel blockers.

Maitotoxin elicited a marked influx of 45Ca2+ into NIH 3T3 fibroblast cells. The influx was blocked by imidazoles (econazole, miconazole, SKF 96365, clotrimazole, calmidazolium) with IC50 values from 0.56 to 3 microM. Phenylalkylamines (verapamil, methoxyverapamil) and nitrendipine were less potent, and diltiazem was very weak. Among other calcium blockers, the diphenylbutylpiperidines fluspirilene and penfluridol, the diphenylpropylpiperidine loperamide, and the local anesthetic proadifen were quite active with IC50 values of 2-4 microM. The pattern of inhibition of maitotoxin-elicited calcium influx did not correspond to the ability of the agents to block elevation of calcium that ensues through calcium-release activated calcium (CRAC) channels after activation of phosphoinositide breakdown by ATP in HL-60 cells. The imidazoles did block CRAC channels, but fluspirilene, penfluridol, loperamide and proadifen were ineffective. Loperamide actually appeared to enhance influx of calcium via the activated CRAC channels. The imidazoles, in particular calmidazolium, caused an apparent influx of calcium and caused a stimulation of phosphoinositide breakdown in HL-60 cells.

3T3 Cells↗