bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of SB‐271046: A potent, selective and orally active 5‐HT6 receptor antagonist
Authors: Routledge Carol , Bromidge Steven M , Moss Stephen F , Price Gary W , Hirst Warren , Newman Helen , Riley Graham , Gager Tracey , Stean Tania , Upton Neil , Clarke Stephen E , Brown Anthony M , Middlemiss Derek N 
Published: January 2005

SB‐271046, potently displaced [3H]‐LSD and [125I]‐SB‐258585 from human 5‐HT6 receptors recombinantly expressed in HeLa cells in vitro (pKi 8.92 and 9.09 respectively). SB‐271046 also displaced [125I]‐SB‐258585 from human caudate putamen and rat and pig striatum membranes (pKi 8.81, 9.02 and 8.55 respectively).
SB‐271046 was over 200 fold selective for the 5‐HT6 receptor vs 55 other receptors, binding sites and ion channels.
In functional studies on human 5‐HT6 receptors SB‐271046 competitively antagonized 5‐HT‐induced stimulation of adenylyl cyclase activity with a pA2 of 8.71.
SB‐271046 produced an increase in seizure threshold over a wide‐dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of 0.1 mg kg−1 p.o. and maximum effect at 4 h post‐dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB‐271046 (EC50 of 0.16 μM) and brain concentrations of 0.01–0.04 μM at Cmax.
These data, together with the observed anticonvulsant activity of other selective 5‐HT6 receptor antagonists, SB‐258510 (10 mg kg−1, 2–6 h pre‐test) and Ro 04‐6790 (1–30 mg kg−1, 1 h pre‐test), in the rat MEST test, suggest that the anticonvulsant properties of SB‐271046 are likely to be mediated by 5‐HT6 receptors.
Overall, these studies demonstrate that SB‐271046 is a potent and selective 5‐HT6 receptor antagonist and is orally active in the rat MEST test. SB‐271046 represents a valuable tool for evaluating the in vivo central function of 5‐HT6 receptors.

British Journal of Pharmacology (2000) 130, 1606–1612; doi:10.1038/sj.bjp.0703457
Effect of venotropic drugs on the respiratory activity of isolated mitochondria and in endothelial cells
Authors: Janssens Dominique , Delaive Edouard , Houbion Andrée , Eliaers François , Remacle José , Michiels Carine 
Published: January 2005

Several drugs used in the treatment of chronic peripheral ischaemic and venous diseases, i.e. aescine, Cyclo 3, Ginkor Fort, hydroxyethylrutosides, naftidrofuryl, naphthoquinone and procyanidolic oligomers, were tested on the mitochondrial respiratory activity.
The results show that all these drugs protected human endothelial cells against the hypoxia‐induced decrease in ATP content. In addition, they all induced a concentration‐dependent increase in respiratory control ratio (RCR) of liver mitochondria pre‐incubated with the drugs for 60 min.
The drugs were divided into two groups according to their effects. The first group (A), comprising aescine, Ginkor Fort, naftidrofuryl and naphthoquinone, increased RCR by decreasing state 4 respiration rate. The second group of drugs (B), comprising hydroxyethylrutosides, procyanidolic oligomers and Cyclo 3, increased RCR by increasing state 3 respiration rate. The drugs of group A were able to prevent the inhibition of complexes I and III respectively by amytal and antimycin A while the first two drugs of group B increased adenine nucleotide translocase activity. Cyclo 3 inhibited the carbonylcyanide m‐chlorophenyl hydrazone (mCCP)‐induced uncoupling of mitochondrial respiration. None of these seven drugs could protect complexes IV and V, respectively, from inhibition by cyanide and oligomycin.
When tested on endothelial cells the drugs of group A, in contrast to group B, prevented the decrease in ATP content induced by amytal or antimycin A.
The present results suggest that the protective effects on mitochondrial respiration activity by these venotropic drugs may explain their protective effect on the cellular ATP content in ischaemic conditions and some of their beneficial therapeutic effect in chronic vascular diseases.

British Journal of Pharmacology (2000) 130, 1513–1524; doi:10.1038/sj.bjp.0703461
Orphanin FQ/nociceptin and [Phe1Ψ(CH2‐NH)Gly2] nociceptin(1‐13)‐NH2 stimulate gastric motor function in anaesthetized rats
Authors: Krowicki Zbigniew K , Kapusta Daniel R , Hornby Pamela J 
Published: January 2005

Orphanin FQ/nociceptin (OFQ/N) is a preferred endogenous ligand for the orphan opioid receptor‐like‐1 receptor. This peptide has been reported to increase intestinal, but not gastric, motor activity.
In the present study, OFQ/N (0.6–60 nmol kg−1 i.v.) increased intragastric pressure and antral contractility and, as expected, decreased blood pressure in anaesthetized rats.
The gastric motor effects of OFQ/N (6 nmol kg−1) were not affected by inhibition of nitric oxide synthase or opioid receptor blockade.
OFQ/N (6 nmol kg−1) evoked gastric motor increases and hypotension were not affected by prior administration of its derivative [Phe1Ψ(CH2‐NH)Gly2]nociceptin‐(1‐13)‐NH2 unless the pseudopepotide was administered shortly (5 min) prior to OFQ/N. This putative antagonist (6–300 nmol kg−1) alone increased antral motility with approximately 100 fold lower potency than OFQ/N.
Neither bilateral vagotomy nor spinal cord transection altered OFQ/N‐evoked increases in intragastric pressure and antral contractility.
In conclusion, OFQ/N induces gastric motor excitation in addition to its known effects to increase intestinal motility. The gastric responses to OFQ/N are not dependent on ‘classical’ opioid receptor activation or nitric oxide, similar to the case for the intestines. The primary site of action of OFQ/N on the stomach is probably via enteric nerves, since central descending vagal or sympathetic pathways are not necessary for OFQ/N to increase gastric motility. The gastric motor effects of the derivative [Phe1Ψ(CH2‐NH)Gly2]nociceptin‐(1‐13)‐NH2 are similar to OFQ/N, although with lower potency. The effects of the derivative as a partial agonist or antagonist in different experimental paradigms may reflect tissue OFQ/N receptor reserve.

British Journal of Pharmacology (2000) 130, 1639–1645; doi:10.1038/sj.bjp.0703463
Inhibition of HERG potassium channels by the antimalarial agent halofantrine
Authors: Tie H , Walker B D , Singleton C B , Valenzuela S M , Bursill J A , Wyse K R , Breit S N , Campbell T J 
Published: January 2005

Halofantrine is a widely used antimalarial agent which has been associated with prolongation of the ‘QT interval’ of the electrocardiogram (ECG), torsades de pointes and sudden death. Whilst QT prolongation is consistent with halofantrine‐induced increases in cardiac ventricular action potential duration, the cellular mechanism for these observations has not been previously reported.
The delayed rectifier potassium channel, IKr, is a primary site of action of drugs causing QT prolongation and is encoded by the human‐ether‐a‐go‐go‐related gene (HERG). We examined the effects of halofantrine on HERG potassium channels stably expressed in Chinese hamster ovary (CHO‐K1) cells.
Halofantrine blocked HERG tail currents elicited on repolarization to −60 mV from +30 mV with an IC50 of 196.9 nM. The therapeutic plasma concentration range for halofantrine is 1.67–2.98 μM.
Channel inhibition by halofantrine exhibited time‐, voltage‐ and use‐dependence. Halofantrine did not alter the time course of channel activation or deactivation, but inactivation was accelerated and there was a 20 mV hyperpolarizing shift in the mid‐activation potential of steady‐state inactivation. Block was enhanced by pulses that render channels inactivated, and channel blockade increased with increasing duration of depolarizing pulses.
We conclude that HERG channel inhibition by halofantrine is the likely underlying cellular mechanism for QT prolongation. Our data suggest preferential binding of halofantrine to the open and inactivated channel states.

British Journal of Pharmacology (2000) 130, 1967–1975; doi:10.1038/sj.bjp.0703470
FK506 potently inhibits T cell activation induced TNF‐α and IL‐1β production in vitro by human peripheral blood mononuclear cells
Authors: Sakuma Shozo , Kato Yasuko , Nishigaki Fusako , Sasakawa Tatsuya , Magari Katsue , Miyata Susumu , Ohkubo Yoshitaka , Goto Toshio 
Published: January 2005

The aim of this study was to elucidate the in vitro inhibitory potency of FK506 on production of the inflammatory cytokines, tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β, with a view to assessing this immunosuppressive agent as a potential anti‐rheumatic drug.
We employed an in vitro model which produces TNF‐α and IL‐1β through T cell activation. Human peripheral blood mononuclear cells (PBMC) were cultured with immobilized anti‐CD3/CD28 monoclonal antibody in this model.
FK506 inhibited anti‐CD3/CD28 induced TNF‐α and IL‐1β production at concentrations less than 1 ng ml−1. Flow cytometric analysis of intracellular TNF‐α and IL‐1β positive cells showed that FK506 potently suppresses inflammatory cytokine production from CD14+ monocytes as well as from T cells.
Cyclosporin A (CsA) and dexamethasone (DEX) also inhibited the anti‐CD3/CD28 induced cytokine production, but were less potent than FK506. FK506 and CsA, but not DEX, specifically inhibited anti‐CD3/CD28 induced inflammatory cytokine production without affecting the lipopolysaccaride (LPS) induced effect. Methotrexate (MTX) was completely inactive for suppressing cytokine production under either condition.
Anti‐CD3/CD28 stimulated PBMC culture supernatants were found to enhance the expression of adhesion molecules in human vascular endothelial cells. FK506, CsA and DEX led to the suppression of adhesion molecule expression probably by inhibiting cytokine production from PBMC.
The inhibitory potency of agents on TNF‐α and IL‐1β production was compared with cytotoxicity and FK506 was not cytotoxic at concentrations several orders of magnitude greater than those required for cytokine inhibition.
These results strongly suggest that FK506 may be most effective to specifically prevent T cell activation mediated inflammatory cytokine production in a clinical setting.

British Journal of Pharmacology (2000) 130, 1655–1663; doi:10.1038/sj.bjp.0703472
Comparison of the pharmacological properties of EDHF‐mediated vasorelaxation in guinea‐pig cerebral and mesenteric resistance vessels
Authors: Dong Hui , Jiang Yanfen , Cole William C , Triggle Christopher R 
Published: January 2005

In the presence of L‐NNA (100 μM), indomethacin (10 μM) and ODQ (10 μM), acetylcholine induced a concentration‐dependent vasorelaxation of guinea‐pig mesenteric and middle cerebral arteries precontracted with cirazoline or histamine, but not with high K+, indicating the contribution of an endothelium‐derived hyperpolarizing factor (EDHF).
In cerebral arteries, charybdotoxin (ChTX; 0.1 μM) completely inhibited the indomethacin, L‐NNA and ODQ‐insensitive relaxation; iberiotoxin (IbTX, 0.1 μM), 4‐aminopyridine (4‐AP, 1 mM), or barium (30 μM) significantly reduced the response; in the mesenteric artery, ChTX and IbTX also reduced this relaxation. Glibenclamide (10 μM) had no affect in either the mesenteric or cerebral artery.
Neither clotrimazole (1 μM) nor 7‐ethoxyresorufin (3 μM) affected EDHF‐mediated relaxation in the mesenteric artery, but abolished or attenuated EDHF‐mediated relaxations in the cerebral artery. AM404 (30 μM), a selective anandamide transport inhibitor, did not affect the vasorelaxation response to acetylcholine in the cerebral artery, but in the mesenteric artery potentiated the vasorelaxation response to acetylcholine in an IbTX, and apamin‐sensitive, but SR 141816A‐insensitive manner. Ouabain (100 μM) almost abolished EDHF‐mediated relaxation in the mesenteric artery, but enhanced the relaxation in the cerebral artery whereas the addition of K+ (5–20 mM) to precontracted guinea‐pig cerebral or mesenteric artery induced further vasoconstriction.
These data suggest that in the guinea‐pig mesenteric and cerebral arteries different EDHFs mediate acetylcholine‐induced relaxation, however, EDHF is unlikely to be mediated by K+.

British Journal of Pharmacology (2000) 130, 1983–1991; doi:10.1038/sj.bjp.0703474
Smooth muscle and parasympathetic nerve terminals in the rat urinary bladder have different subtypes of α1 adrenoceptors
Authors: Széll E A , Yamamoto T , De Groat W C , Somogyi G T 
Published: January 2005

Neurally evoked contractions and release of 3H‐ acetylcholine (ACh) during electrical field stimulation were measured in rat urinary bladder strips.
The α1 agonist phenylephrine (PE, 2–8 μM) increased the amplitude of neurally evoked contractions, facilitated the release of ACh and increased the baseline tone of the bladder strips.
The PE‐induced facilitation of the contractions did not significantly change during a prolonged exposure to PE (120 min), whereas the PE‐induced rise in baseline tone gradually decreased to 65% of the initial value.
Low concentrations of specific α1A antagonists, 5‐methyl urapidil (5‐MU), REC15/2739 and WB‐4101 competitively inhibited the facilitation of the neurally‐evoked contractions (pA2: 8.77; 9.59 and 9.62, respectively), whereas higher concentrations of 5‐MU (IC50: 48 nM) were required to suppress the PE‐rise in baseline. WB‐4101 (100 μM) inhibited the PE‐induced facilitation of ACh release.
The irreversible α1B antagonist chloroethyl‐clonidine (CEC, 10–50 μM) inhibited the PE‐evoked rise in base line tone, but did not affect the PE‐induced facilitation of the neurally evoked contractions nor the facilitation of ACh release. However, CEC increased the area and amplitude of the neurally‐evoked contractions by 261±33 and 47.2±8.4%, respectively. Atropine significantly inhibited the CEC evoked increase in area and amplitude of the electrically evoked contractions (76.5±4.8 and 40.8±3%, respectively) indicating that CEC facilitated the cholinergic responses of the electrically stimulated bladder strips.
It is concluded that α1A and CEC sensitive α1B and/or α1D adrenoceptors are expressed in the rat bladder in different locations. On the cholinergic nerve terminals α1A adrenoceptors mediate prejunctional facilitation, whereas postjunctional α1B/α1D adrenoceptors mediate smooth muscle contraction.

British Journal of Pharmacology (2000) 130, 1685–1691; doi:10.1038/sj.bjp.0703475
Effects of BDF 9198 on action potentials and ionic currents from guinea‐pig isolated ventricular myocytes
Authors: Yuill K H , Convery M K , Dooley P C , Doggrell S A , Hancox J C 
Published: January 2005

BDF 9198 (a congener of DPI 201–106 and BDF 9148) was found to be a positive inotrope on guinea‐pig isolated ventricular muscle strips. The effects of BDF 9198 on action potentials and ionic currents from guinea‐pig isolated ventricular myocytes were studied using the whole cell patch clamp method.
In normal external solution, at 37°C, action potential duration at 50% repolarization (APD50) was 167.4±8.36 ms (n=37). BDF 9198 produced a concentration‐dependent increase in APD50 (no significant increase at 1×10−10 M; and APD50 values of 273.03±35.8 ms at 1×10−9 M; n=6, P<0.01 and 694.7±86.3 ms at 1×10−7 M; P<0.001, n=7). At higher concentrations in the range tested, BDF 9198 also induced early and delayed and after‐depolarizations.
Qualitative measurements of INa with physiological [Na]o showed prolongation of the current by BDF 9198, and the appearance of transient oscillatory inward currents at high concentrations.
Quantitative recording conditions for INa were established using low external [Na] and by making measurements at room temperature. The current–voltage relation, activation parameters and time‐course of INa were similar before and after a partial blocking dose of Tetrodotoxin (TTX, 1 μM), despite a 2 fold difference in current amplitude. This suggests that voltage‐clamp during flow of INa was adequately maintained under our conditions.
Selective measurements of INa at room temperature showed that BDF 9198 induced a concentration‐dependent, sustained component of INa (ILate) and caused a slight left‐ward shift in the current–voltage relation for peak current. The drug‐induced ILate showed a similar voltage dependence to peak current in the presence of BDF 9198. Both peak current and ILate were abolished by 30 μM TTX and were sensitive to external [Na].
Inactivation of control INa during a 200 ms test pulse to −30 mV followed a bi‐exponential time‐course. In addition to inducing a sustained current component, BDF 9198 left the magnitude of the fast inactivation time‐constant unchanged, but increased the magnitude of the slow inactivation time‐constant. Additional experiments with a longer pulse (1 s) raised the possibility that in the presence of BDF 9198, INa inactivation may be comprised of more than two phases.
No significant effects of 1×10−6 M BDF 9198 were observed on the L‐type calcium current, or delayed and inward rectifying potassium currents measured at 37°C.
It is concluded that the prolongation of APD50 by BDF 9198 resulted from selective modulation of INa. Reduced current inactivation induced a persistent INa, increasing the net depolarizing current during the action potential. This action of the drug indicates a potential for ‘QT prolongation’ of the ECG. The observation of after‐depolarizations suggests a potential for proarrhythmia at some drug concentrations.

British Journal of Pharmacology (2000) 130, 1753–1766; doi:10.1038/sj.bjp.0703476
Evidence against a role of inducible nitric oxide synthase in the endothelial protective effects of delayed preconditioning
Authors: Laude Karine , Richard Vincent , Henry Jean‐Paul , Lallemand Françoise , Thuillez Christian 
Published: January 2005

Preconditioning the heart with brief periods of ischaemia induces delayed endothelial protection against reperfusion injury, but the precise mechanisms involved in this endogenous protein are still unclear. Induction of the type II‐nitric oxide synthase (iNOS) acts as a mediator of the preconditioning against myocardial infarction and stunning. The present study was designed to assess whether iNOS also contributes to the delayed endothelial protective effects of preconditioning.
Rats were subjected to 20 min ischaemia followed by 60 min reperfusion 24 h after sham surgery or preconditioning (one cycle or 2 min ischaemia/5 min reperfusion and two cycles of 5 min ischaemia/5 min reperfusion). At the end of the reperfusion, coronary segments were removed distal to the site of occlusion and mounted in wire myographs.
Ischaemia‐reperfusion (I/R) decreased the endothelium‐dependent relaxations to acetylcholine (maximal relaxations: sham, 66±5%; I/R, 40±1%; P<0.05) and this impairment was prevented by preconditioning (maximal relaxation: 61±6%).
Administration of N‐(3‐aminomethyl)benzyl)acetaminide (1400W), a highly selective inhibitor for iNOS, 10 min before prolonged ischaemia did not modify the beneficial effect of preconditioning (maximal relaxation: 66±5%).
These data show that preconditioning induces delayed protection against reperfusion‐injury. However, in contrast to the myocytes, these endothelial protective effects of delayed preconditioning do not involve iNOS.

British Journal of Pharmacology (2000) 130, 1547–1552; doi:10.1038/sj.bjp.0703477
Cytochrome P450 inactivation by serum from humans with a viral infection and serum from rabbits with a turpentine‐induced inflammation: the role of cytokines
Authors: Bleau Anne‐Marie , Levitchi Mihaela C , Maurice Hélène , Du Souich Patrick 
Published: January 2005

Serum from humans with an acute upper respiratory viral infection and from rabbits with turpentine‐induced inflammation reduce the catalytic activity of hepatic cytochrome P450 (P450). The aim of this study was to identify the serum mediators responsible for the decrease in P450 activity.
Rabbit and human sera were fractionated by size exclusion chromatography and the fractions tested for their ability to reduce the activity and amount of P450 after 4 h of incubation with hepatocytes from turpentine‐treated rabbits (HINF). Rabbit and human sera decreased P450 activity by around 40% without any change in the amount of CYP1A1 and 1A2 apoproteins.
In rabbit serum, the fraction containing proteins of Mr 23–15 kDa decreased P450 content by 41%, but did not alter the amount of the apoproteins. Anti‐IL‐6 antibody added to the Mr 23–15 kDa fraction restored P450 content to 97% of control values, while anti‐IL‐1β, TNF‐α and IFN‐γ antibodies had no effect. Supporting the role of IL‐6, incubation of HINF in the presence of IL‐6 for 4 h reduced P450 content by 40%.
In human serum, the fraction containing proteins of Mr >95 kDa lowered P450 content by 43% without modifying the amounts of CYP1A1/2. Neutralization experiments showed that IFN‐γ, IL‐6, and IL‐1β contributed to the decrease in P450 content.
In conclusion, the present results demonstrate that IL‐6, and IFN‐γ, IL‐6 and IL‐1β are the serum mediators released in vivo by a turpentine‐induced inflammatory reaction in the rabbit and an upper respiratory viral infection in humans, respectively, inactivating hepatic P450.

British Journal of Pharmacology (2000) 130, 1777–1784; doi:10.1038/sj.bjp.0703486
Neurotoxic activity of venom from the Australian Eastern mouse spider (Missulena bradleyi) involves modulation of sodium channel gating
Authors: Rash Lachlan D , Birinyi‐Strachan Liesl C , Nicholson Graham M , Hodgson Wayne C 
Published: January 2005

Mouse spiders represent a potential cause of serious envenomation in humans. This study examined the activity of Missulena bradleyi venom in several in vitro preparations. Whilst female M. bradleyi venom at doses up to 0.05 μl ml−1 failed to alter twitch or resting tension in all preparations used, male venom (0.02 and 0.05 μl ml−1) produced potent effects on transmitter release in both smooth and skeletal neuromuscular preparations.
In the mouse phrenic nerve diaphragm preparation, male M. bradleyi venom (0.02 μl ml−1) caused rapid fasciculations and an increase in indirectly evoked twitches.
Male venom (0.02 and 0.05 μl ml−1) also caused a large contracture and rapid decrease in indirectly evoked twitches in the chick biventer cervicis muscle, however had no effect on responses to exogenous ACh (1 mM) or potassium chloride (40 mM). In the chick preparation, contractile responses to male M. bradleyi venom (0.05 μl ml−1) were attenuated by (+)‐tubocurarine (100 μM) and by tetrodotoxin (TTX, 1 μM). Both actions of male M. bradleyi venom were blocked by Atrax robustus antivenom (2 units ml−1).
In the unstimulated rat vas deferens, male venom (0.05 μl ml−1) caused contractions which were inhibited by a combination of prazosin (0.3 μM) and P2X‐receptor desensitization (with α,β‐methylene ATP 10 μM). In the rat stimulated vas deferens, male venom (0.05 μl ml−1) augmented indirectly evoked twitches.
Male venom (0.1 μl ml−1) causes a slowing of inactivation of TTX‐sensitive sodium currents in acutely dissociated rat dorsal root ganglion neurons.
These results suggest that venom from male M. bradleyi contains a potent neurotoxin which facilitates neurotransmitter release by modifying TTX‐sensitive sodium channel gating. This action is similar to that of the δ‐atracotoxins from Australian funnel‐web spiders.

British Journal of Pharmacology (2000) 130, 1817–1824; doi:10.1038/sj.bjp.0703494