Abstract:
:The antinociceptive profile of selected histamine H(2) and histamine H(3) receptor antagonists led to the discovery of improgan, a non-brain-penetrating analgesic agent which does not act on known histamine receptors. Because no chemical congener of improgan has yet been discovered which has both antinociceptive and brain-penetrating properties, the present study investigated the antinociceptive effects of a series of chemical compounds related to zolantidine, a brain-penetrating histamine H(2) receptor antagonist. The drugs studied presently contain the piperidinomethylphenoxy (PMPO) moiety, hypothesized to introduce brain-penetrating characteristics. Following intracerebroventricular (i.c.v.) dosing in rats, six of eight drugs produced dose- and time-related antinociception on both the tail flick and hot plate tests over a nearly eight-fold range of potencies. Ataxia and other motor side effects were observed after high doses of these drugs, but two of the compounds (SKF94674 and loxtidine) produced maximal antinociception at doses which were completely devoid of these motor effects. Consistent with the hypothesis that PMPO-containing drugs are brain-penetrating analgesics, SKF94674 and another derivative (JB-9322) showed dose-dependent antinociceptive activity 15 to 30 min after systemic dosing in mice, but these effects were accompanied by seizures and death beginning 45 min after dosing. Other drugs showed a similar pattern of antinociceptive and toxic effects. In addition, loxtidine produced seizures without antinociception, whereas zolantidine produced neither effect after systemic dosing in mice. Although several of the drugs tested have histamine H(2) receptor antagonist activity, neither the antinociception nor the toxicity was correlated with histamine H(2) receptor activity. The present results are the first to demonstrate the existence of brain-penetrating antinociceptive agents chemically related to zolantidine and improgan, but further studies are needed to understand the mechanisms of both the pain relief and toxicity produced by these agents.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Hough LB,Nalwalk JW,Lu Q,Shan Z,Svokos K,Wentland MP,Montero MJdoi
10.1016/j.ejphar.2005.08.040keywords:
subject
Has Abstractpub_date
2005-10-17 00:00:00pages
38-46issue
1-3eissn
0014-2999issn
1879-0712pii
S0014-2999(05)00893-9journal_volume
522pub_type
杂志文章abstract::5-methoxy-N,N-dimethyltryptamine (5-MeODMT) produced a dose-dependent decrease in the discharge rate of serotonin-containing neurons in the dorsal raphe nucleus of freely moving cats. This ranged from a 15% decrease at 10 microgran/kg, i.m., to a virtual complete depression of activity at 250 microgram/kg. 5-MeODMT's ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(79)90406-0
更新日期:1979-02-15 00:00:00
abstract::The influence of the membrane environment on the alpha 1-adrenoceptor has been investigated by examining the effect of phospholipase digestion on the binding of [3H]prazosin to aortic and hepatic membranes. Membrane digestion by phospholipase A2 and phospholipase C was found to markedly reduce prazosin binding to the ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0922-4106(92)90079-b
更新日期:1992-05-12 00:00:00
abstract::We have examined the effects of intrathecally (i.t.) administered CP-96,345, a non-peptide NK1 receptor ligand, on the spinal nociceptive flexor reflex and on the facilitation of this reflex evoked by i.t. substance P (SP), neurokinin A (NKA) and electrical conditioning stimulation of cutaneous C-afferents. CP-96,345 ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(92)90428-7
更新日期:1992-06-17 00:00:00
abstract::To investigate whether argatroban ((2R,4R)-4-methyl-1-[N(2)-((RS)-3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid hydrate, a selective thrombin inhibitor, exerts a direct action on phenotype conversion of vascular smooth muscle cells, cultured rabbit aortic vascular smooth muscl...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(03)01293-7
更新日期:2003-02-07 00:00:00
abstract::The NMDA receptor agonist quinolinic acid (9 mM) was infused i.c.v. via ALZET osmotic minipumps for 2 weeks. This treatment produced a persistent, short-term memory deficit in the T-maze. Autoradiography revealed a decrease in the density of choline uptake sites in the hippocampus. Parallel s.c. infusion by another mi...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(95)00682-6
更新日期:1996-01-18 00:00:00
abstract::We recently reported that tumor necrosis factor alpha is able to cause a dose-dependent and persistent reduction in gap junctional intercellular communication between primary human smooth muscle cells. In order to study whether this observed persistent reduction in gap junctional intercellular communication is a uniqu...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(96)00368-8
更新日期:1996-08-22 00:00:00
abstract::The involvement of essential sulfhydryl groups in alpha 2-adrenoceptor function was investigated in the cerebral cortex of 7 and 70 day old rats. N-Ethylmaleimide (NEM) inhibited specific [3H]clonidine binding to cerebral cortical membranes in a concentration-dependent and biphasic manner in both infant and adult rats...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(83)90169-3
更新日期:1983-08-05 00:00:00
abstract::Presynaptic cholinergic markers could be used for estimating the integrity of the cholinergic systems in the human brain with brain imaging techniques such as Single-photon emission computed tomography (SPECT). Vesamicol, an inhibitor of the vesicular acetylcholine transporter, and some of its derivatives have been su...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(97)81946-2
更新日期:1997-11-05 00:00:00
abstract::Fibroblast growth factor 21 (FGF21) has been identified as a potent and robust metabolic regulator. Administration of recombinant FGF21 protein to rodents and rhesus monkeys exerts strong anti-diabetic effects. Previous studies have demonstrated that FGF21 inhibits glucose output in the rat H4IIE hepatoma cell line. W...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2012.11.065
更新日期:2013-02-28 00:00:00
abstract::Intradermal application of nociceptin was used to investigate its in vivo effect on the inflammatory response in rats. Intradermal nociceptin (5 pmol/site-5 nmol/site) increased vascular permeability in a dose-dependent manner. The increased vascular permeability by nociceptin (5 nmol/site) was dose-dependently inhibi...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(00)00746-9
更新日期:2000-11-03 00:00:00
abstract::Following pretreatment with 6-OH-dopamine, the sympathetic nerve endings of the iris and skeletal muscle of mice and rats were not longer detectable by cytochemistry for noradrenaline. In the same animals, the specific binding of [3H] ouabain to intact soleus muscles was not significantly different from that measured ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(81)90571-9
更新日期:1981-07-10 00:00:00
abstract::DSP-4 (N-(2-chloroethyl)-ethyl-2-bromobenzylamine) a novel neurotoxin which destroys central noradrenaline neurones after peripheral injection was administered to rats (50 mg/kg X 2). This procedure did not alter activity responses to quipazine (7.5 mg/kg) or apomorphine (0.2 mg/kg) but prevented their enhancement by ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(85)90593-x
更新日期:1985-09-10 00:00:00
abstract::The specificity of action of extrinsic acetylcholine on extrajunctional and junctional receptors in the chick biventer cervicis muscle was studied by determining its ability to protect the responses evoked by acetylcholine and by tetanic nerve stimulation from the blockade by alpha-bungarotoxin, an irreversible bindin...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(75)90178-8
更新日期:1975-09-01 00:00:00
abstract::The present studies demonstrate that adenylate cyclase and cyclic 3',5'-adenosine monophosphate (cAMP)-phosphodiesterase activities in dog bronchus are comparable to those found in other smooth muscle preparations. Catecholamines, in the order isoproterenol greater than epinephrine greater than norepinephrine, increas...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(77)90368-5
更新日期:1977-01-07 00:00:00
abstract::The effect of cannabinoid receptor activation and blockade on the propulsive activity in the mouse small intestine was assessed in the present study by measuring the transit of an orally administered, non-absorbable marker. The cannabinoid receptor agonist WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(97)01555-0
更新日期:1998-02-26 00:00:00
abstract::Substance P and its tachykinin NK(1) receptors are highly expressed in brain regions involved in emotional control. We recently showed that NK(1)-mediated substance P neurotransmission is deeply involved in the control of aggressiveness. To get further insights into the NK(1) receptor/aggression relationship, we studi...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2009.03.050
更新日期:2009-06-02 00:00:00
abstract::An excess of lipids may accumulate in the kidney in conditions such as diabetes and hypertension, and can potentially cause renal injury. We previously reported that an infusion of angiotensin II into a rat induced deposition of lipids in the renal tubular epithelial cells. Here we have examined the effect of pioglita...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2012.02.027
更新日期:2012-05-05 00:00:00
abstract::In the brains of normal and reserpinized rats both diazepam and amino-oxyacetic acid (AOAA) decreased the 5-hydroxytryptophan (5HTP) accumulation induced by the decarboxylase inhibitor 3-hydroxybenzylhydrazine (NSD 1015). In reserpinized animals, the action of diazepam was antagonized by picrotoxin and bicuculline in ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(79)90200-0
更新日期:1979-05-01 00:00:00
abstract::Pancreatic adenocarcinoma is a leading cause of cancer death in the United States and represents a challenging chemotherapeutic problem. The pharmacological control of angiogenesis might represent a novel approach to the management of pancreas cancer, since the pathological development of vascular supply is a critical...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2004.07.062
更新日期:2004-09-13 00:00:00
abstract::Calcium entry blockers can effectively preserve high-energy phosphates in ischemic heart. However, little is known about the optimal timing of drug therapy. The moment of nisoldipine administration in relation to its protective efficacy during ischemia and reperfusion was studied in rat hearts. Nisoldipine (50 nM), gi...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(85)90662-4
更新日期:1985-11-26 00:00:00
abstract::The effect of apomorphine (ap) was investigated in rats kept in a familiar cage; 0.25-5 mg/kg s.c. produced a short-lasting, abnormal hypermotility consisting mainly of locomotion and sniffing without grooming. Ap was administered to rate pretreated s.c. with various drugs. Ap hypermotility was antagonized by 12 neuro...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(76)90092-3
更新日期:1976-04-01 00:00:00
abstract::Hyperphosphatemia is associated with severe decline of renal function in chronic kidney disease and elevates cardiovascular mortality. Type II sodium dependent phosphate transporter 2A (Npt2A) plays a major role in renal phosphate reabsorption and could be explored as a target for anti-hyperphosphatemia therapy. Human...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2013.09.005
更新日期:2013-12-05 00:00:00
abstract::Platycodi Radix is the root of Platycodon grandiflorum and it is widely used in the traditional Oriental medicine as an expectorant for pulmonary diseases and a remedy for respiratory disorders. Platycodin D is the major constituent of triterpene saponins in the root. This study investigates apoptosis by platycodin D ...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2006.03.012
更新日期:2006-05-10 00:00:00
abstract::Renal hemodynamics were studied using an electromagnetic perivascular flow sensor in anesthetized rats injected i.v. with vehicle, 5 or 10 mg/kg body weight (b.w.) sulindac. No hemodynamic changes occurred with vehicle (n = 6), but mean arterial pressure was significantly decreased (by 15 mmHg) with sulindac (n = 12)....
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(97)00178-7
更新日期:1997-07-09 00:00:00
abstract::We hypothesized that uncompetitive NMDA glutamate receptor antagonists memantine (2,5-dimethyl-1-adamantanamine), and amino-alkyl-cyclohexane compounds: MRZ 2/579 (1-amino-1,3,3,5,5-pentamethylcyclohexane HCl), MRZ 2/600 (1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane HCl), and MRZ 2/615 (1-amino-1,3,5,5-tetramethyl-3...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/s0014-2999(02)02121-0
更新日期:2002-09-27 00:00:00
abstract::Acute administration of fluoxetine (1, 10 and 20 mg/kg i.p.) increased extracellular levels of serotonin (5-hydroxytryptamine, 5-HT) in the frontal cortex, ventral hippocampus and raphe nuclei as measured by in vivo microdialysis in anaesthetized rats. In the frontal cortex, fluoxetine showed a marked dose-response ef...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(95)00573-4
更新日期:1995-11-14 00:00:00
abstract::The Langendorff-perfused rabbit heart preparation has been used to study the interaction of isolated rabbit neutrophils with regionally ischaemic myocardium. Short durations of regional ischaemia (10-60 min) and subsequent reperfusion (30 min) of the hearts with neutrophils resulted in a significant time-dependent acc...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(92)94835-j
更新日期:1992-11-17 00:00:00
abstract::This study determined the in vitro functional profile of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolinone monomethanesulfonate (OPC-14523) at rat and human serotonin (5-HT) 5-HT1A receptors and binding affinity of OPC-14523 at human frontocortical 5-HT1A receptors. OPC-14523 (1 microM...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/j.ejphar.2005.05.035
更新日期:2005-07-11 00:00:00
abstract::In previous studies, we have shown that opioid agonists ([D-Ala2, D-Leu5]enkephalin (DADLE), [D-Ser2, Leu5]enkephalin-Thr6 (DSLET), ethylketocyclazocine and etorphine) bind to opioid binding sites and decrease cell proliferation of human T47D breast cancer cells. Furthermore, we provided evidence about a cross-reactio...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(96)00339-1
更新日期:1996-08-29 00:00:00
abstract::Pretreatment of chick biventer cervicis preparations with ethanol (290 mM) potentiated the EC50 of choline, acetylcholine, carbachol and phenyltrimethylammonium 91%, 319%, 97% and 213%, respectively. Perhaps this interaction of ethanol and neurotransmitter could contribute to the effects on coordination and motor acti...
journal_title:European journal of pharmacology
pub_type: 杂志文章
doi:10.1016/0014-2999(80)90165-x
更新日期:1980-01-25 00:00:00