A5084417962- Adenosine and Purinergic Signaling
- Antiplatelet Therapy and Cardiovascular Diseases
- Nitric Oxide and Endothelin Effects
- Eicosanoids and Hypertension Pharmacology
- Synthesis of β-Lactam Compounds
- Receptor Mechanisms and Signaling
- Cardiac electrophysiology and arrhythmias
- Platelet Disorders and Treatments
- Heart Failure Treatment and Management
- Acute Myocardial Infarction Research
- Inflammatory mediators and NSAID effects
- Glaucoma and retinal disorders
- Renin-Angiotensin System Studies
- Lipoproteins and Cardiovascular Health
- Cerebral Venous Sinus Thrombosis
- Infection Control and Ventilation
- Restless Legs Syndrome Research
- Neuroscience of respiration and sleep
- Nausea and vomiting management
- Pharmacological Receptor Mechanisms and Effects
- Diabetes Treatment and Management
- Intraocular Surgery and Lenses
- Cardiovascular Issues in Pregnancy
- Electroconvulsive Therapy Studies
- Pharmacology and Obesity Treatment
AstraZeneca (Brazil)
2001-2023
Cambridge University Hospitals NHS Foundation Trust
2021
University of Cambridge
2019
Loughborough University
1995-2007
AstraZeneca (United Kingdom)
2000-2007
Cleveland Clinic
2003
Research & Development Institute
1994
Walgreens Boots Alliance (United Kingdom)
1981
The platelet P2T receptor plays a major role in aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We explored analogues of adenosine triphosphate (ATP), which is weak, nonselective but competitive antagonist. Modification the polyphosphate side chain prevent breakdown agonist diphosphate (ADP) substitution adenine moiety enhance affinity selectivity for led identification 10e (AR-C67085MX), having an IC50 2.5 nM against...
Dopexamine is an agonist at peripheral dopamine receptors and β 2 ‐adrenoceptors. has approximately one‐third the potency of in stimulating vascular DA 1 ‐receptor dog, resulting a fall renal resistance 20% 2.3 × 10 −8 mol kg −1 (i.a.). Prejunctional ‐receptors are also stimulated by dopexamine, reduction neurogenic vasoconstriction rabbit isolated ear artery (IC 50 1.15 −6 M) tachycardia cat (ID 5.4 , i.v.), with six four times less respectively than that dopamine. By contrast, dopexamine...
In the present study we have classified receptor(s) mediating increases in intracellular calcium concentration ([Ca 2+ ] i ) human washed platelets and compared pharmacological profile obtained with that observed Jurkat cells, stably transfected a bovine P2Y 1 ‐receptor. The ‐receptor antagonist, adenosine‐3′‐phosphate‐5′‐phosphate (A3P5P), competitively antagonized agonist responses both similar affinities (pK B of 5.8 6.0, respectively). selective ADP AR‐C66096, exhibited partial agonism...
ADP‐dependent platelet aggregation is mediated by the P 2T ‐purinoceptor and specifically inhibited ATP, which a competitive antagonist. However, ATP functions as an agonist at other 2 subtypes in tissues is, therefore, non‐selective. This paper describes effects of novel analogue, FPL 66096 (2‐propylthio‐D‐β,γ‐difluoromethylene ATP), on ADP‐induced ADP‐independent human washed platelets standard preparations containing 2X ‐ (rabbit ear artery) 2Y ‐purinoceptors (guinea‐pig aorta). In...
The cardiovascular effects of dopexamine and dopamine were compared in the anaesthetized conscious dog by use intravenous infusions over dose range 3 × 10 −9 − −7 mol kg −1 min . In dog, produced a dose‐related fall blood pressure due to peripheral vasodilatation small rise heart rate contractility. By contrast, did not significantly reduce but larger increase At highest infusion (10 ) increased dopamine. Dopexamine dilated renal mesenteric vascular beds with potency similar that Femoral...
In the present study we have investigated roles of P2Y 1 and P 2T receptor subtypes in adenosine 5′‐diphosphate (ADP)‐induced aggregation human platelets heparinized platelet rich plasma. The response to ADP can be characterized as initial rate or maximum final extent aggregation. profile is determined by concentration used, being transient at lower sustained higher concentrations. antagonist, adenosine‐3′‐phosphate‐5′‐phosphate (A3P5P) competitively antagonized (pK B 5.47) transformed a...
Journal of Aerosol Medicine and Pulmonary Drug DeliveryVol. 33, No. 4 Letters to the EditorFree AccessUrgent Appeal from International Society for Aerosols in (ISAM) During COVID-19: Clinical Decision Makers Governmental Agencies Should Consider Inhaled Route Administration: A Statement ISAM Regulatory Standardization Issues Networking GroupJolyon P. Mitchell, Ariel Berlinski, Sebastian Canisius, David Cipolla, Myrna B. Dolovich, Igor Gonda, Guenther Hochhaus, Nani Kadrichu, Svetlana...
Objective— Reperfusion therapy for myocardial infarction is limited by a significant reocclusion rate and less optimal tissue perfusion due to excessive platelet accumulation recruitment at the sites of vascular injury. We assessed influence selective P2Y 12 -receptor antagonist (AR-C69931MX), in conjunction with thrombolytic therapy, on prevention aggregation thrombus formation. Methods Results— A canine coronary electrolytic injury thrombosis model was used. Tissue-type plasminogen...
1. The role of endogenous ADP in platelet aggregation vivo remains unclear due to the lack suitable P2T-antagonist probes. This paper describes potency, selectivity and specificity novel P 2T-purinoceptor antagonist, FPL 67085 (2-propylthio-D-beta,gamma-dichloromethylene ATP) both vitro anaesthetized rat vivo. 2. (3-30 nM) produced concentration-dependent rightward displacement concentration-effect (E/[A]) curve for ADP-induced human washed platelets with no effect on ADP-independent at < or...
Intravenous infusion of L-NG-nitro-arginine, an inhibitor endothelial nitric oxide (NO) synthesis, produced vasoconstriction in the coronary, cerebral, renal and duodenal vascular beds conscious rabbit. In this study, using radiolabelled microspheres, we provide vivo evidence for a basal NO-dependent vasodilator tone coronary bed.
P2Y receptor activation in many cell types leads to phospholipase C and accumulation of inositol phosphates, while blood platelets, C6‐2B glioma cells, B10 microvascular endothelial cells a subtype, which couples inhibition adenylyl cyclase, historically termed AC , (P2T or P 2T platelets) has been identified. Recently, this cloned designated 12 keeping with current P2 nomenclature. Three selective antagonists, range affinities, inhibited ADP‐induced aggregation washed human rat...
P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Receptors [3, 5]) are activated endogenous ligands ATP, ADP, uridine triphosphate, diphosphate and UDP-glucose. The relationship of many cloned to endogenously expressed is not yet established so it might be appropriate use wording such 'uridine triphosphate-preferring (or ATP-, etc.) receptor' or 'P2Y1-like', etc., until further, undefined, corroborative criteria can applied [46, 109, 187, 375, 388].Clinically used drugs...
We examined the effect of substance P, a potent stimulator endothelium-derived relaxing factor (EDRF) release, on responses to collagen and adenosine 3′, 5′-diphosphate (ADP) in an vivo model platelet aggregation. Substance P inhibited aggregation induced by both ADP. This anti-platelet was particularly pronounced against collagen-induced prevented prior administration haemoglobin (Hb), known inhibitor EDRF-mediated responses. Collagen-induced vitro unaffected concentration equivalent that...
A novel technique is described in which the effect of β-adrenoceptor antagonists timolol and carteolol, vasodilators sodium nitroprusside (SNP) verapamil on intraocular pressure (IOP) distribution ocular flow bovine arterially perfused eye investigated using radiolabelled microspheres. At maximum IOP-reducing dose was found to significantly reduce perfusion choroid and, at higher dose, it iris. By contrast, a maximal carteolol markedly reduced iris, ciliary body choroid. Vasoconstriction...
P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Receptors [3, 5, 192]) are activated endogenous ligands ATP, ADP, uridine triphosphate, diphosphate and UDP-glucose. The relationship of many cloned to endogenously expressed is not yet established so it might be appropriate use wording such 'uridine triphosphate-preferring (or ATP-, etc.) receptor' or 'P2Y1-like', etc., until further, undefined, corroborative criteria can applied [47, 110, 190, 383, 396]. Clinically used...
P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Receptors [3, 5, 189]) are activated endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. The eight mammalian distinct nucleotides: P2Y1, P2Y11, P2Y12 P2Y13 adenosine-nucleotides; P2Y2, P2Y4 can be both adenosine uridine nucleotides, with some species-specific differences; P2Y6 is mainly UDP; P2Y14 preferentially sugar-uracil nucleotides. missing numbers in receptor nomenclature refer either to non-mammalian...
The cardiovascular effects of FPL 62129, a novel dihydropyridine calcium channel blocker. were studied in chloralose-anaesthetised dogs comparison with those nifedipine. 62129 and nifedipine produced dose-related falls blood pressure total peripheral resistance similar potency these respects. While the vasodilator accompanied by reflex tachycardia. reduced without altering heart rate. Both compounds increased cardiac contractility output. Nifedipine PR interval duration ECG, whereas no...
Abstract FPL67085MX represents the first in a class of novel, highly potent and selective P2T purinoceptor antagonists which are inhibitors adenosine diphosphate (ADP)-induced platelet aggregation in-vitro. In an early series compounds we studied effect variation adenine 2-substituent on potency derived quantitative structure-activity relationships (QSARs) between properties molecules their biological activity. This work has recently been revisited using comparative molecular-field analysis...