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At least 289 records · Page 16Linked to original sources
PubMed1999

Effects of choline and other nicotinic agonists on the tectum of juvenile and adult Xenopus frogs: a patch-clamp study.

We have used anatomical methods and whole-cell patch-clamp recording to assess the distribution of nicotinic receptors in the tectum of Xenopus frogs and to measure effects of nicotinic ligands (carbachol, cytisine and nicotine) on glutamatergic spontaneous miniature excitatory postsynaptic currents. Our results confirm that retinotectal axons account for the majority of nicotinic receptors in the tectum and that nicotinic agonists exert presynaptic effects that increase the rate of transmitter release on to tectal cells. The nicotinic blockers mecamylamine and methyllycaconitine reduced responses to carbachol and cytisine. A small percentage of cells also showed postsynaptic responses. We have assessed whether there are developmental changes in the frequency of occurrence of spontaneous miniature excitatory postsynaptic currents. The first three months post-metamorphosis fall within the critical period for the dramatic plasticity displayed by binocular inputs during development in Xenopus. During this period, visual activity governs the formation of orderly maps relayed from the ipsilateral eye via the cholinergic projection from the nucleus isthmi to the tectum. In this study, we have found that critical-period tecta (two to 12 weeks postmetamorphosis) tend to have higher spontaneous activity than do older tecta (two to 69 weeks postmetamorphosis), and that nicotinic agonists increase that activity in both groups, with the result that the peak rates in response to nicotinic agonists are higher during the critical period than later. We also investigated the possible role of choline as an agonist of nicotinic receptors in the tectum. We have found that choline, as well as carbachol and cytisine, can cause a reversible increase in the rate of miniature excitatory postsynaptic currents. This result may help to explain how the isthmotectal projection, which accounts for the overwhelming majority of cholinergic input to the tectum, can exert effects on retinotectal terminals even though there are no morphologically identifiable synapses between the two populations. We have examined the morphology of cells filled with biocytin during the patch-clamp experiments, and we find that cells with dendrites in the stratum zonale, a layer with particularly dense input from the contralateral nucleus isthmi, have higher spontaneous activity than cells with dendrites that do not extend into that layer. Nicotinic agonists increased the activity recorded in both classes of cells. In addition, four pretectal cells were identified. Nicotinic agonists increased the rate of spontaneous activity recorded in that population. The results indicate that retinotectal transmission in the superior colliculus can be increased presynaptically by activity of the cholinergic projections of the nucleus isthmi. This modulation may be the basis for observations that blocking of cholinergic input disrupts the formation of topographic retinotectal projections. Moreover, the ability of choline to activate these receptors suggests that this metabolite of acetylcholine may permit paracrine activation of presynaptic receptors even though the tectum contains high acetylcholinesterase activity.

Aging↗
PubMed1999

Autoradiographic comparison of [3H](-)nicotine, [3H]cytisine and [3H]epibatidine binding in relation to vesicular acetylcholine transport sites in the temporal cortex in Alzheimer's disease.

The laminar binding distribution of three nicotinic receptor agonists, [3H](-)nicotine, [3H]cytisine, and [3H]epibatidine, and their relation to the [3H]vesamicol binding, which is known to represent the vesicular acetylcholine transport sites, was performed employing in vitro autoradiography on the medial temporal cortex (Brodmann area 21). Autopsied brain tissue from nine Alzheimer patients and seven age-matched controls were used. The binding pattern of the three nicotinic ligands in the normal cortex was in general similar, showing binding maxima in the cortical layers I, III and V. The binding of [3H](-)nicotine, [3H]cytisine, and [3H]epibatidine was lower in the older controls and more uniform throughout the layers as compared with younger controls. There was a significant age-related decrease in the binding of the three nicotinic ligands within the controls (age range: 58 to 89 years; P[3H](-)nicotine = 0.002, P[3H]epibatidine = 0.010, P[3H]cytisine = 0.037). In the older controls, the [3H]epibatidine binding was much decreased as compared with that of [3H](-)nicotine and [3H]cytisine. This may indicate a higher selectivity of [3H]epibatidine for a nicotinic receptor subtype that is particularly affected by aging. The laminar binding pattern of [3H]vesamicol showed one maximum in the outer cortical layers II/III. The [3H]vesamicol binding did not change with aging. The binding of all ligands was significantly decreased in all layers of the temporal cortex in Alzheimer's disease, but the [3H]vesamicol binding decreased only half as much as the nicotinic receptors. Also, choline acetyltransferase activity was percentually more reduced than [3H]vesamicol binding in Alzheimer's disease. The cortical laminar binding pattern of all 3H-ligands was largely absent in the Alzheimer's disease cases. The less severe loss of vesicular acetylcholine transport sites as compared with the loss of the nicotinic receptors and choline acetyltransferase activity may suggest that vesamicol binding sites might be more preserved in presynaptic terminals still existing and thereby expressing compensatory capacity to maintain cholinergic activity.

Acetylcholine↗
PubMed2002

The effects of heroin on prolactin levels in male rhesus monkeys: use of cumulative-dosing procedures.

There is considerable evidence that mu opioid receptors are involved in the regulation of anterior pituitary function. For example, in nonhuman primates and humans, mu agonists generally increase prolactin (PRL) levels. In contrast, mu antagonists decrease or have no effect on PRL levels. The goal of this study was to assess the potential utility of cumulative-dosing procedures to evaluate the endocrine effects of mu opioid receptor ligands. The effects of single and multiple, cumulative doses of the mu agonist heroin and the mu-selective antagonist quadazocine on PRL levels were investigated in four male rhesus monkeys. Cumulative dose-response curves were determined by infusing increasing drug doses at 60 min intervals over 290 min. Blood samples for PRL analysis were collected at 25 and 50 min after each cumulative infusion. Samples were collected at similar time points following single drug dose administration. Heroin (0.01-0.32 mg/kg, IV) administration dose-dependently increased PRL levels. Maximum levels of heroin-induced PRL levels were equivalent after single and cumulative doses. Quadazocine alone (0.032-1.0 mg/kg, IM) did not alter PRL levels significantly. However, quadazocine (0.1 mg/kg, IM) antagonized heroin-stimulated increases in PRL levels and produced a significant rightward shift in the heroin dose-effect curve. These data suggest that a cumulative-dosing procedure similar to that used in behavioral pharmacology may be useful to study the endocrine pharmacology of mu opioids in rhesus monkeys.

Animals↗
PubMed2003

Effects of heroin and its metabolites on schedule-controlled responding and thermal nociception in rhesus monkeys: sensitivity to antagonism by quadazocine, naltrindole and beta-funaltrexamine.

Recent studies have reported differences in the receptor mechanisms and intrinsic efficacies of heroin and its metabolites 6-acetylmorphine and morphine in rodents. The present study examined the generality of these findings to rhesus monkeys using two behavioral procedures. In an assay of schedule-controlled behavior, response rates were recorded under a fixed-ratio 30 schedule of food presentation. In an assay of thermal nociception, tail-withdrawal latencies were measured from warm water (42-58 degrees C). Heroin, 6-acetylmorphine and morphine produced dose-dependent rate-decreasing and antinociceptive effects. Antagonism studies were conducted with the competitive mu-selective antagonist quadazocine, the competitive delta-selective antagonist naltrindole, and the irreversible mu-selective antagonist beta-funaltrexamine (beta-FNA). Quadazocine dose-dependently antagonized the effects of all three opioids. Quadazocine pA2 values were similar across drugs and assays (7.4-7.8) and similar to quadazocine pA2 values for antagonism of other mu agonists. In contrast, naltrindole did not alter the effects of any of the opioids. beta-FNA antagonized the rate-decreasing and antinociceptive effects of heroin and morphine. Dose-effect data for heroin- and morphine-induced antinociception alone and after beta-FNA treatment were used to estimate in vivo apparent efficacy values (tau). Tau values (95% confidence limits) were 8.1 (6.9-9.6) for heroin and 2.6 (2.5-2.9) for morphine, but this difference is relatively small. These results suggest that the rate-decreasing and antinociceptive effects of heroin, 6-acetylmorphine and morphine are mediated by pharmacologically similar populations of mu opioid receptors in rhesus monkeys. The in vivo apparent efficacy of heroin at mu receptors was similar to or only slightly greater than that of morphine.

Animals↗
PubMed1997

Analysis of aporphine and quinolizidine alkaloids from Caulophyllum thalictroides by densitometry and HPLC.

High-performance liquid chromatographic (HPLC) and densitometry procedures were developed to determine the principal alkaloids in the roots of C. thalictroides. In both techniques the alkaloids content was assessed using cytisine as an internal standard. The purity and identity of the peaks of the alkaloids was examined by diode array detection and by comparison with the standards. The content of individual alkaloids was found to be in the range 0.02-1.1% w/w.

Alkaloids↗
PubMed1999

Effects of flupenthixol and quadazocine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys.

The simultaneous i.v. administration of heroin and cocaine, called "speedball," is often reported clinically, and identification of effective pharmacotherapies for polydrug abuse is a continuing challenge. This study compared the effects of treatment using combinations of dopamine and opioid antagonists with each antagonist alone on speedball self-administration by rhesus monkeys. Speedballs (0.01 mg/kg/inj cocaine and 0.0032 mg/kg/inj heroin) and food (1 g banana pellets) were available in four daily sessions on a second-order schedule of reinforcement [FR4 (VR16:S)]. Monkeys were treated for 10 days with saline or ascending 1:10 dose combinations of the dopamine antagonist flupenthixol and the opioid antagonist quadazocine. The combination of flupenthixol (0.018 mg/kg/day) + quadazocine (0.18 mg/kg/day) significantly reduced speedball self-administration in comparison to the saline treatment baseline (p < .05), whereas, the same doses of each antagonist alone had no significant effect on speedball-maintained responding. Treatment with 0.018 mg/kg/day flupenthixol + 0.18 mg/kg/day quadazocine produced a 3-fold rightward shift in the speedball (3:1 cocaine-heroin combination) dose-effect curve. Food-maintained responding was similar during treatment with saline and with flupenthixol + quadazocine combinations. These findings suggest that medication mixtures designed to target both the stimulant and opioid component of the speedball combination, may be an effective approach to polydrug abuse treatment.

Animals↗
PubMed2001

Enhanced biodegradation of cyclotetramethylenetetranitramine (HMX) under mixed electron-acceptor condition.

The biodegradation of cyclotetramethylenetetranitramine, commonly known as 'high melting explosive' (HMX), under various electron-acceptor conditions was investigated using enrichment cultures developed from the anaerobic digester sludge of Thibodaux sewage treatment plant. The results indicated that the HMX was biodegraded under sulfate reducing, nitrate reducing, fermenting, methanogenic, and mixed electron accepting conditions. However, the rates of degradation varied among the various conditions studied. The fastest removal of HMX (from 22 ppm on day 0 to < 0.05 ppm on day 11) was observed under mixed electron-acceptor conditions, followed in order by sulfate reducing, fermenting, methanogenic, and nitrate reducing conditions. Under aerobic conditions, HMX was not biodegraded, which indicated that HMX degradation takes place under anaerobic conditions via reduction. HMX was converted to methanol and chloroform under mixed electron-acceptor conditions. This study showed evidence for HMX degradation under anaerobic conditions in a mixed microbial population system similar to any contaminated field sites, where a heterogeneous population exists.

Anaerobiosis↗
PubMed2003

Rigidified acetylcholine mimics: conformational requirements for binding to neuronal nicotinic receptors.

Rigidified derivatives have been designed and synthesized assuming the g+t conformer of acetylcholine (N-C-C-O=+60 degrees, C-C-O-C=180 degrees ) as active conformation for binding to cytisine sensitive neuronal nicotinic receptors. The SAR of the compounds evaluated, along with those of more flexible analogues, support the g+t conformer hypothesis and highlight the stringent steric limitation of this nicotinic receptor sub-type. Compound 3e has low microM affinity for cytisine sensitive nicotinic receptor binding sites while being selective with regard to the alpha-bungarotoxin sensitive subclass. We also report few compounds with microM affinity for the alpha-bungarotoxin sensitive subclass.

Acetylcholine↗
PubMed1998

A novel series of 6-methoxy-1H-benzotriazole-5-carboxamide derivatives with dual antiemetic and gastroprokinetic activities.

A novel series of 6-methoxy-1H-benzotriazole-5-carboxamide derivatives with a medium perhydroazacycle ring in the amine moiety were prepared, and their antiemetic and gastroprokinetic activities were evaluated. Among them, N-(1-ethylhexahydroazepin-3-yl)-, N-(1-ethyloctahydroazocin-3-yl)- and N-(1-ethyloctahydroazonin-3-yl)-6-methoxy-1H-benzotriazole-5-carbo xamides (24, 36, 37) showed a potent antiemetic activity (inhibition of apomorphine-induced emesis in dogs) along with gastroprokinetic activity (gastric emptying in rats).

Animals↗
PubMed1998

Structure-activity studies related to ABT-594, a potent nonopioid analgesic agent: effect of pyridine and azetidine ring substitutions on nicotinic acetylcholine receptor binding affinity and analgesic activity in mice.

Analogs of A-98593 (1) and its enantiomer ABT-594 (2) with diverse substituents on the pyridine ring were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay. Numerous types of modifications were consistent with high affinity for [3H]cytisine binding sites. By contrast, only selected modifications resulted in retention of analgesic potency in the same range as 1 and 2. Analogs of 2 with one or two methyl substituents at the 3-position of the azetidine ring also were prepared and found to be substantially less active in both assays.

Alkaloids↗
PubMed2003

N-(trifluoromethyl)benzyl substituted N-normetazocines and N-norketobemidones.

To further investigate the unusual profile of N-benzyl substituted opioids, N-trifluoromethylbenzyl normetazocines and norketobemidones were prepared. The introduction of trifluoromethyl substituents on the benzyl group of the (-)-metazocines reduced affinity at all three receptors, with the greatest loss at kappa receptors. Surprisingly, some of the (+)-normetazocines actually possessed higher affinity than the corresponding (-)-isomers. In the ketobemidone series, the effects were different-the 4-trifluoromethyl substituted ketobemidone actually possessed 3-fold higher mu affinity than the unsubstituted parent to give a ligand with good mu affinity. In functional in vitro assays, this compound was a weak antagonists, but in apparent contradiction it was inactive in in vivo assays.

Analgesics, Opioid↗
PubMed1997

TRH mimetics: differentiation of antiamnesic potency from antidepressant effect.

For the purpose of rational modification of the TRH molecule, we were pursuing an approach that consists of two steps: (1) 'obligatory' replacement of histidine with glutamine in TRH and (2) the application of conformational constraints for putative bioactive conformation I stabilized by an intramolecular hydrogen bond between C-terminal carboxamide proton and alpha-carbonyl of histidyl (glutaminyl), and conformation II formed by an intramolecular hydrogen bond between alpha-carbonyl of pyroglutamyl and prolinamide proton. Significant antiamnesic potency was discovered in the passive avoidance test (ECS and Scopolamine induced amnesia) for conformation II mimic (8S,10aS)-8-carbamoyl-1,2,3,6,7,8,9,10a- octahydro-5H,10H-pyrrolo[1,2-a][1,4]diazocin-5,10-dione (2) at doses of 0.1 and 1.0 mg/kg. EEG analysis indicates a mild activating effect of compound 2 on EEG, which is similar to that of piracetam and differs from hard amphetamine activation. Conformation I mimic 3-(2-carbamoylethyl)-2,3,6,7,8,8a-hexahydro-1H,4H-pyrrolo[1,2-a] pyrazin-1,4-dione (1) exhibited an antidepressant effect at a dose of 1 mg/kg. The transition from two putative quasi-cyclic bioactive conformations of TRH and its obligatory similar analogue [Gln2]-TRH to their cyclic mimics led to differentiation of antiamnesic and antidepressant activity of TRH.

Amino Acid Sequence↗
PubMed1998

Synthesis and structure-activity data of some new epibatidine analogues.

The high-pressure Diels-Alder reaction of N-carbomethyoxypyrroles and phenyl vinyl sulfone affords versatile intermediates for the palladium-catalyzed preparation of new epibatidine analogues. Structure-activity relationships of new epibatidine analogues are presented. High affinities of Ki = 0.81 and 2.6 nM for the [3H]-cytisine rat brain nicotinic acetylcholine binding sites were found for the 5-pyrimidinyl and the 5-(2-amino)-pyrimidinyl epibatidine analogues, respectively.

Alkaloids↗
PubMed1998

Calcium sensitization as new principle of inotropic therapy in end-stage heart failure?

OBJECTIVE: Due to shortage of donor hearts and increasing waiting-lists of patients with end-stage heart disease, new pharmacological principles for bridging therapies are necessary. The positive inotropic effects of cAMP-increasing drugs (e.g. catecholamines, phosphodiesterase-inhibitors) are diminished in the failing myocardium. Hence, we investigated the usefulness and mechanism of the two calcium sensitizers, levosimendan and CGP 48506 in preparations from end-stage failing human hearts since the exact mechanism of the positive inotropic effects is not yet clearly understood. METHODS: Failing human hearts which required orthotopic heart transplantation due to idiopathic dilated cardiomyopathy were investigated. Contraction experiments were performed using muscle strips of ventricles. Calcium sensitization was investigated in skinned fibers and phosphodiesterase activity was measured in ventricular homogenate. In addition, cAMP levels were quantified in myocytes from guinea-pig hearts. RESULTS: In muscle stripes from failing human hearts levosimendan (10 micromol/l) increased the force of contraction only to 112.8 +/- 6.7% of predrug values. In contrast, CGP 48506 increased the force of contraction to 311 +/- 59% of predrug values at 100 micromol/l. The time to peak tension and time of relaxation were increased to 175 +/- 4% and 205 +/- 15% of control levels at 100 micromol/l. Skinned fibers from failing human hearts were sensitized to calcium with an EC50 of 10 micromol/l. Other mechanisms of action were excluded since CGP 48506 affected neither the activity of phosphodiesterase isoenzymes I-IV in failing human hearts, nor cAMP levels in guinea-pig cardiomyocytes. On the other hand, levosimendan (1 micromol/l) increased cAMP content from 6.3 +/- 0.3 to 8.1 +/- 0.3 pmol/mg protein. CONCLUSION: CGP 48506 is an inotropic agent with calcium-sensitizing properties in the human heart, that is devoid of inhibitory activity on human cardiac phosphodiesterase isoenzymes. It offers, therefore, a new form of positive inotropic therapy that can be useful for the bridging treatment of heart failure before transplantation. On the other hand, levosimendan is a calcium sensitizer showing less-effective inotropic effects accompanied by increased cAMP levels.

Azocines↗
PubMed1999

Pharmacologic evaluation of isometric contraction-relaxation coupling indexes in rabbit ventricular muscle.

Investigations of the coupling between contraction and relaxation (contraction-relaxation [CRC] process) in isometric conditions are essential in determining whether pharmacologic interventions or cardiac diseases specifically modify isometric relaxation (intrinsic lusitropic effect) or change it in proportion with the accompanying changes in contractility (or inotropy). For this purpose, the CRC process is quantified by various indexes, derived from differentiation and/or curve fitting the whole or relaxation phase of the isometric twitch, one of the most used being tau, the time constant of the final iso(volu)metric phase of relaxation. Nevertheless, the possible redundancy and validity of such indexes have not been thoroughly investigated. Accordingly, we performed a pharmacologic evaluation of such indexes in isolated rabbit ventricular muscles isometrically contracting in vitro, using modifiers of either intracellular Ca(2)+ handling (nifedipine, ryanodine, 2,5-di-tert-butyl-benzohydroquinone, all negative inotropic compounds, and BAY K 8644, a positive inotropic drug), or myofibrillar Ca(2)+ sensitivity (CGP 48506, a Ca(2)+ sensitizer, and butanedione monoxime, a Ca(2)+ desensitizer, respectively positive and negative inotropic compounds). The isometric twitch in control conditions and in the presence of increasing concentration of each compound was analyzed to determine the classically used CRC and/or lusitropic indexes, derived either from single parameters such as the maximal rate or contraction and relaxation (+dT(max) and -dT(max), respectively), or from curve fitting of the whole, or part, of the twitch. As the rate of isometric relaxation is dependent on myofilament properties, we expected that compounds modifying myofibrillar Ca(2)+ sensitivity in an opposite direction (CGP 48506 vs butanedione monoxime) would be the only drugs exerting an intrinsic lusitropic and opposite effect on a validated CRC index. Results showed that (1) none of the tested compounds affected the slope of the linear relationship between peak twitch tension and dT(max), a previously assumed CRC index, sensitive only to myofibrillar Ca(2)+ sensitivity modifiers; (2) the lusitropic parameter B, derived from mathematical curve fitting of the whole isometric twitch, and the ratio +dT(max)/dT(max), exhibited similar drug- and dose-dependency, but no opposite sensitivity to CGP 48506 and BDM for either index; and (3) negative inotropic compounds dose-dependently slowed relaxation (and conversely for positive inotropes), whether the latter was quantified by the rate constant beta, derived from double exponential curve fitting of the whole relaxation phase, or by the time constants tau(L) and tau(E), derived from the curve fitting (logistic and monoexponential, respectively) of the final phase of relaxation. Nevertheless, the pharmacologicly induced changes in beta were statistically significant at lower concentrations and exhibited less individual variability, compared with the time constants. We demonstrate that intrinsic lusitropic changes can be quantified by the value of the slope of the relationship relating beta to peak isometric tension: the slope value was unchanged by Ca(2)+ handling modifiers, decreased by CGP 48506, and reversed by BDM (indicating number, negative, and positive intrinsic lusitropic effects respectively). Based on these data, we propose that the linear relationship between beta and peak isometric tension could be used a new method to assess whether pharmacologic interventions or cardiac diseases exert intrinsic effects on isometric relaxation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2005

From ligand design to therapeutic efficacy: the challenge for nicotinic receptor research.

S-Nicotine, the principal psychoactive constituent of Nicotiana tabacum, underpins addiction to tobacco smoking. Although tobacco consumption is a leading cause of death worldwide, nicotine itself is also proposed to have potential therapeutic benefits for a diverse range of conditions. Nicotine interacts with its cognate receptors in the central nervous system to exert a predominantly modulatory influence, making neuronal nicotinic receptors attractive therapeutic targets. Here, we focus on three natural products as lead compounds for drug discovery programs, nicotine, epibatidine and cytisine, and consider the aims and limitations that shape these drug discovery endeavors.

Alkaloids↗