Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of different doses of buspirone, 3-dipropyl-amino-5-hydrochromar (NDO 008) and 8-hydroxydipropyl-aminotetralin (8-OH-DPAT) (administered intraperitoneally) were studied in tests of anxiolytic and antidepressant action in rats. These tests included the elavated plus maze test, the forced swim test, stress-induced suppression of open-field behavior, and the differential-reinforcement-of-low-rates-of-behaviour-72 sec (DRL 72 s) test. Buspirone (0.125 mg/kg) and NDO 008 (1.0 to 2.0 mg/kg) produced anxiolytic activity in the elevated plus maze, whereas 8-OH-DPAT did not in the doses employed. All three compounds increased activity in the forced swim test, although buspirone did so at a lower dose than NDO 008 and 8-OH-DPAT. In the stress-induced suppression test of open field activity all three compounds induced an antidepressant-like effect at different doses dependent on whether footshock (stressor) was presented 24 hr before or just prior to the open-field test. All three compounds even caused some reduction of activity in the non-shocked rats. 8-OH-DPAT (1.0 mg/kg) produced a significant and reliable increase in the Reinforcement/Response rate quotient in the DRL 72s test. These diverse results may provide an indication of potential clinical efficacy of the 5-HT1A agonists in the treatment of anxiety and depression.
 ...
PMID:5-Hydroxytryptamine1A receptor agonists in animal models of depression and anxiety. 138 35

A series of N6-(p-sulfophenyl)alkyl and N6-sulfoalkyl derivatives of adenosine was synthesized, revealing that N6-(p-sulfophenyl)adenosine (10b) is a moderately potent (Ki vs [3H]PIA in rat cortical membranes was 74nM) and A1-selective (120-fold) adenosine agonist, of exceptional aqueous solubility of > 1.5 g/mL (approximately 3 M). Compound 10b was very potent in inhibiting synaptic potentials in gerbil hippocampal slices with an IC50 of 63 nM. At a dose of 0.1 mg/kg ip in rats, 10b inhibited lipolysis (a peripheral A1 effect) by 85% after 1 h. This in vivo effect was reversed using the peripherally selective A1-antagonist 1,3-dipropyl-8-[p-(carboxyethynyl)phenyl]xanthine (BW1433). The same dose of 10b in NIH Swiss mice (ip) was nearly inactive in locomotor depression, an effect that has been shown to be centrally mediated when elicited by lower doses of other potent adenosine agonists, such as N6-cyclohexyladenosine (CHA) (Nikodijevic et al. FEBS Lett. 1990, 261, 67). HPLC studies of biodistribution of a closely related and less potent homologue, N6-[4-(p-sulfophenyl)butyl]adenosine indicated that a 25 mg/kg ip dose in mice resulted in a plasma concentration after 30 min of 0.46 micrograms/mL and no detectable drug in the brain (detection limit < 0.1% of plasma level). Although 10b at doses > 0.1 mg/kg in mice depressed locomotor activity, this depression was unlike the effects of CHA and was reversible by BW1433. These data suggest that 10b is a potent adenosine agonist in vivo and shows poor CNS penetration.
 ...
PMID:Synthesis and biological activity of N6-(p-sulfophenyl)alkyl and N6-sulfoalkyl derivatives of adenosine: water-soluble and peripherally selective adenosine agonists. 143 17

The effects of 5-amino-4-imidazolecarboxamide riboside (rAICA) on coronary adenosine efflux were examined in blood-free perfused working rat heart preparations subjected to mild (70% O2) and severe hypoxia (45% O2). Under these hypoxic conditions, no significant increase of coronary adenosine effluxes was observed in the presence of 300 microM rAICA alone. However, rAICA-induced augmentation of coronary adenosine efflux during hypoxia was revealed in the presence of an adenosine deaminase inhibitor, erythro-(2-hydroxy-3-nonyl)adenine hydrochloride, indicating that the failure to note the increase in coronary adenosine efflux was due to a rapid deamination of adenosine to inosine. A depression in heart rate during mild and severe hypoxia was significantly exacerbated by rAICA. These effects on heart rate were mediated by adenosine, since they were effectively blocked by 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine, a selective adenosine A1-receptor antagonist. These results suggest that rAICA elevates adenosine efflux during hypoxia.
 ...
PMID:5-Amino-4-imidazolecarboxamide riboside raises adenosine in perfused hypoxic rat heart. 180 58

Adenosine analogs, such as N6-cyclohexyladenosine (CHA) that are selective for A1-adenosine receptors, and analogs, such as 5'-N-ethylcarboxamidoadenosine (NECA) that are active at both A1 and A2 receptors, cause a profound depression of locomotor activity in mice via a central mechanism. The depression is effectively reversed by non-selective adenosine antagonists such as theophylline. We report that 2-([2-aminoethylamino) carbonylethylphenylethylamino]-5'-N-ethylcarboxamidoadenosine (APEC), an amine derivative of the A2-selective agonist, CGS21680, is a potent locomotor depressant in mice. The in vivo pharmacology is consistent with A2-selectivity at a central site of action. Two parameters indicative of locomotor activity, horizontal activity and total distance travelled, were measured using a computerized activity monitor. From dose-response curves it was found that APEC (ED50 16 micrograms/kg) is more potent than CHA (ED50 60 micrograms/kg) and less potent than NECA (ED50 2 micrograms/kg). The locomotor depression by APEC was reversible by theophylline, but not by the A1-selective antagonists 8-cyclopentyltheophylline (CPT) and 8-cyclopentyl-1, 3-dipropyl-2-thioxanthine, nor by the peripheral antagonists 8-p-sulfophenyltheophylline (8-PST) and 1,3-dipropyl-8-p-sulfophenylxanthine. The locomotor activity depression elicited by NECA and CHA was reversed by A1-selective antagonists. These results suggest that the effects of APEC are due to stimulation of A2 adenosine receptors in the brain.
 ...
PMID:Characterization of the locomotor depression produced by an A2-selective adenosine agonist. 230 37

In halothane-nitrous oxide-anesthetized pigs, the effect of the competitive adenosine antagonist, BW-A1433U (a derivative of 1,3-dipropyl-8-phenylxanthine), on postdefibrillation bradyarrhythmia and hemodynamic depression was investigated. In protocol 1, repetitive episodes of ventricular fibrillation lasting 15 seconds before transthoracic DC shock were performed in five animals, before (control) and after the administration of BW-A1433U (5 mg/kg i.v.). An unsuccessful initial shock was immediately followed by a rescue shock of 40 A. In ventricular fibrillation episodes requiring rescue shocks, nine of 19 episodes (47%) exhibited second- or third-degree atrioventricular block at 15 seconds postdefibrillation compared with only one of 16 BW-A1433U episodes (6%). In protocol 2, the effect of BW-A1433U was determined in the presence of dipyridamole, a nucleoside uptake blocker known to potentiate the cardiac actions of adenosine. To counter the hypotensive effect of dipyridamole, methoxamine was continuously infused at 0.015 mg/kg/min i.v. Sequential episodes of ventricular fibrillation lasting 45 seconds were terminated by shocks of 40 A in the presence of methoxamine alone, after dipyridamole (1.5-7.5 mg i.v.), and after BW-A1433U (5 mg/kg i.v.). Over the first 15 seconds postdefibrillation, BW-A1433U significantly (p less than 0.05) increased the number of spontaneous beats (31 +/- 2) and systolic/diastolic blood pressure (111 +/- 4/67 +/- 5 mm Hg; mean +/- SEM; n = 9) compared with both methoxamine (16 +/- 2 beats; 98 +/- 14/52 +/- 12 mm Hg; n = 5) and dipyridamole (8 +/- 3 beats; 58 +/- 11/27 +/- 6 mm Hg; n = 9), respectively. Rapid infusion of BW-A1433U during dipyridamole postdefibrillation periods raised heart rate and blood pressure to preventricular fibrillation levels within 30 seconds. Thus, BW-A1433U can reverse and prevent postdefibrillation bradyarrhythmia and hemodynamic depression. Endogenous adenosine may be an important mediator of postdefibrillation cardiovascular collapse.
 ...
PMID:Role of endogenous adenosine in postdefibrillation bradyarrhythmia and hemodynamic depression. 273 45

Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors.
 ...
PMID:Adenosine receptors: development of selective agonists and antagonists. 358 7

A comparison of structure-choleretic activity relationship has been made for several branched- and straight-chain carboxylic acids including valproic acid. Cumulative bile flow was 13.8, 23.8, 29.4 and 14.9 ml/4hr/kg body weight for dimethyl-, diethyl-, dipropyl- (valproic acid), and dibutyl-acetic acid, respectively, after iv administration of approximately equimolar doses (1100 mumoles/kg). Except for dibutylacetic acid, maximal bile flow increased from control rates of 50-60 to 120-140 microliters/min/kg. Administration of higher doses of 2,2-dimethylbutanoic acid and 2-ethylbutanoic acid did not increase maximal bile flow above 125-140 microliters/min/kg but did prolong the duration of choleresis. Maximal and cumulative bile flows increased with length of carboxylic acid chain for 2,2-dimethyl substituted acids (2,2-dimethylacetic acid to 2,2-dimethylbutanoic acid). If the two methyl groups were on C-3 (3-methylbutanoic acid), no change in bile flow was observed. Straight-chain acids from C-5 to C-11 and pent-4-enoic acid did not alter bile flow. Thus, the effectiveness of several branched-chain carboxylic acids as choleretics parallel their ability as anticonvulsants. In contrast, the straight-chain acids which cause central nervous system depression have no choleretic activity.
 ...
PMID:Choleretic effect of structural analogs of valproic acid in the rat. 640 71

An in vitro slice preparation of rat amygdala was used to study the actions of forskolin and cyclic adenosine-3',5'-monophosphate (cAMP) analogues on the N-methyl-D-aspartate (NMDA) receptor-mediated synaptic potential (EPSPNMDA). Intracellular recordings were made from basolateral amygdala neurons in the presence of 6-cyano-7-nitroquinoxaline-2,3-di-one (CNQX, 10 microM) and picrotoxin (50 microM) to pharmacologically isolate the EPSPNMDA. Application of forskolin (25 microM) markedly and persistently potentiated the EPSPNMDA. In contrast, the inactive forskolin analogue, 1,9-dideoxy-forskolin, failed to affect the EPSPNMDA significantly. Superfusion of dibutyryl-cAMP (dbcAMP, 200 microM) for 15 min caused a transient depression of the amplitude of EPSPNMDA. The EPSPNMDA amplitude was reduced to 68 +/- 3% of control (n = 10) 15 min after the application, restored to its control value within 25 min, and followed by a long-term potentiation (LTP). Pretreating the slices with 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX, 5 microM), a selective A1 receptor antagonist, blocked the transient depressive phase produced by dbcAMP. This result suggests that the transient depression induced by dbcAMP was likely due to the interaction of dbcAMP or its breakdown products with adenosine A1 receptors. To determine the site of action, we examined the effect of forskolin on the postsynaptic responses to exogenously applied NMDA. Forskolin potentiated the postsynaptic depolarization induced by NMDA, suggesting that the enhancement is mediated, at least in part, by a persistent upregulation of postsynaptic NMDA receptor-operated conductances. Occlusion experiments were performed to examine whether the sustained enhancements of EPSP(NMDA) produced by tetanic stimulation (TS) and forskolin share a common mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cyclic adenosine-3',5'-monophosphate potentiates the synaptic potential mediated by NMDA receptors in the amygdala. 762 88

Excitatory amino acids may cause neuronal damage and death in cerebral hypoxia and ischemia, through the activation of different subtypes of glutamate receptors, in particular of the N-methyl-D-aspartate (NMDA) receptor. In the present work, the effect of hypoxia on the component of the field excitatory postsynaptic potential (fepsp) mediated by the NMDA receptor was studied in the hippocampal CA1 area of the rat. A period of 15 min of hypoxia induced virtual abolition of the NMDA receptor-mediated fepsp and a 94.8 +/- 0.7% maximal decrease in the fepsp. A period of 3 min of hypoxia induced a 89.3 +/- 12.3% maximal decrease in the NMDA receptor-mediated component of the fepsp and only a 50.8 +/- 11.5% maximal decrease in the fepsp. Both periods of hypoxia thus induced a more pronounced depression of the NMDA receptor-mediated component of the fepsp than of the fepsp. We found that 48.5 +/- 9.1% decrease (about half of the total decrease) in the NMDA receptor-mediated fepsp, and 51.6 +/- 19.6% decrease (approximately all decrease) in the fepsp induced by hypoxia (3 min) were reversed in the presence of the selective adenosine A1 receptor antagonist, 1,3-dipropyl-8- cyclopentylxanthine (DPCPX) (50 nM), and thus likely to be mediated by endogenous adenosine, through the activation of adenosine A1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:1,3-Dipropyl-8-cyclopentylxanthine attenuates the NMDA response to hypoxia in the rat hippocampus. 783 77

We previously reported that adenosine has significant depressor effects in the nucleus tractus solitarii and area postrema of the rat. The purpose of this study was to determine whether the spontaneously hypertensive rat (SHR) has abnormalities in medullary sensitivity to adenosine. Male SHR and Wistar-Kyoto (WKY) rats (aged 12 to 15 weeks) were anesthetized with urethane, and blood pressure was monitored intraarterially. Stereotaxic microinjection (60 nL) of adenosine was made into the nucleus tractus solitarii and the area postrema and was confirmed histologically. Dose-related decreases in mean blood pressure and heart rate occurred in both strains tested, and this effect was completely abolished by 1,3-dipropyl- 8-p-sulfophenylxanthine (0.92 nmol), a potent adenosine receptor antagonist. However, there were significant differences between SHR and WKY rats in the magnitude of blood pressure and heart rate depression. A similar pattern of response was found in the area postrema. Thus, adenosine is a potent depressor agent in the nucleus tractus solitarii and area postrema of rats, and adenosine has significantly fewer depressor effects in SHR. These data suggest that alterations in purinergic mechanisms of central cardiovascular control exist in the SHR model.
 ...
PMID:Attenuated cardiovascular response to adenosine in the brain stem nuclei of spontaneously hypertensive rats. 784 79


1 2 3 4 5 Next >>