“…While a number of distinct classes of P2 antagonists have been described (Figures −5), these are frequently lacking in both selectivity for, and between, P2 receptors. , The effects of both P2 receptor agonists and antagonists also show significant tissue and species dependency that further complicates pharmacological classification. , In contrast, the discovery of the alkylxanthines, caffeine, and theophylline, as adenosine receptor antagonists in the 1970s, , provided a concrete basis for an extensive effort in P1 (adenosine) receptor medicinal chemistry, resulting in the identification of several clinical drug candidates based on the xanthine pharmacophore some 20 years before the cloning of this receptor family . Furthermore, synthetic chemistry efforts in the area of nucleoside triphosphates have been somewhat limited, with a systematic focus on developing structure−activity relationships for the various P2 receptors and high-throughput screening approaches to identifying novel pharmacophores being relatively recent. ,,− 2 (A) Structures of selected adenine nucleotides modified on the phosphate moiety that have been investigated as P2 receptor agonists. (B) Structures of selected adenine nucleotides modified on the base and ribose moieties that have been investigated as P2 receptor agonists.…”
Section: Evolution Of the P2 Receptor Familymentioning
confidence: 99%
“…The latter was refined in 1978 with the delineation of distinct P1 (adenosine) and P2 (ATP) receptor classes . However, it is only in the past decade that definitive evidence for a family of discrete molecular targets responsive to ATP and other nucleotides, the P2 purinergic receptor family, has been obtained using molecular biological, pharmacological, and medicinal chemistry approaches. − Thus, there is now a wealth of compelling data to support a role for extracellular purine (ATP, ADP 2 ) and pyrimidine (UTP 5 , UDP 6 ) nucleotides acting as neurotransmitter/neuromodulators to modulate the function of a diversity of mammalian cell types and tissues under both normal and pathophysiological conditions. ,− 1 Metabolic interconversion of naturally occurring purine and pyrimidine nucleotides of relevance to extracellular action. Purine (adenosine derivatives, 1 − 4 ) and pyrimidine (uridine derivatives, 5 and 6 ) nucleosides and nucleotide are shown.…”
Section: Introductionmentioning
confidence: 99%
“…In the current Perspective, advances in the understanding of the molecular biology, physiology, and function of the P2 purinergic receptor family in the decade since the last Perspective on purinergic receptors are reviewed together with ongoing medicinal chemistry efforts in identifying novel agonists and antagonists. In addition, the therapeutic potential for P2 receptor ligands, including ATP and UTP (Figure ) and receptor antagonists, in a variety of human disease states that include cancer, chronic obstructive pulmonary disease (COPD), chronic bronchitis, asthma, bladder and erectile dysfunction, reproduction, auditory and ocular function, pain, hemostasis (platelet aggregation, neutropenia and leukemia), neurodegeneration, and immune system function are reviewed. An alternative, complementary approach to the discovery of novel drugs interacting with the P2 receptor system is that of targeting the enzymes modulating ATP (and UTP) metabolism.…”
“…While a number of distinct classes of P2 antagonists have been described (Figures −5), these are frequently lacking in both selectivity for, and between, P2 receptors. , The effects of both P2 receptor agonists and antagonists also show significant tissue and species dependency that further complicates pharmacological classification. , In contrast, the discovery of the alkylxanthines, caffeine, and theophylline, as adenosine receptor antagonists in the 1970s, , provided a concrete basis for an extensive effort in P1 (adenosine) receptor medicinal chemistry, resulting in the identification of several clinical drug candidates based on the xanthine pharmacophore some 20 years before the cloning of this receptor family . Furthermore, synthetic chemistry efforts in the area of nucleoside triphosphates have been somewhat limited, with a systematic focus on developing structure−activity relationships for the various P2 receptors and high-throughput screening approaches to identifying novel pharmacophores being relatively recent. ,,− 2 (A) Structures of selected adenine nucleotides modified on the phosphate moiety that have been investigated as P2 receptor agonists. (B) Structures of selected adenine nucleotides modified on the base and ribose moieties that have been investigated as P2 receptor agonists.…”
Section: Evolution Of the P2 Receptor Familymentioning
confidence: 99%
“…The latter was refined in 1978 with the delineation of distinct P1 (adenosine) and P2 (ATP) receptor classes . However, it is only in the past decade that definitive evidence for a family of discrete molecular targets responsive to ATP and other nucleotides, the P2 purinergic receptor family, has been obtained using molecular biological, pharmacological, and medicinal chemistry approaches. − Thus, there is now a wealth of compelling data to support a role for extracellular purine (ATP, ADP 2 ) and pyrimidine (UTP 5 , UDP 6 ) nucleotides acting as neurotransmitter/neuromodulators to modulate the function of a diversity of mammalian cell types and tissues under both normal and pathophysiological conditions. ,− 1 Metabolic interconversion of naturally occurring purine and pyrimidine nucleotides of relevance to extracellular action. Purine (adenosine derivatives, 1 − 4 ) and pyrimidine (uridine derivatives, 5 and 6 ) nucleosides and nucleotide are shown.…”
Section: Introductionmentioning
confidence: 99%
“…In the current Perspective, advances in the understanding of the molecular biology, physiology, and function of the P2 purinergic receptor family in the decade since the last Perspective on purinergic receptors are reviewed together with ongoing medicinal chemistry efforts in identifying novel agonists and antagonists. In addition, the therapeutic potential for P2 receptor ligands, including ATP and UTP (Figure ) and receptor antagonists, in a variety of human disease states that include cancer, chronic obstructive pulmonary disease (COPD), chronic bronchitis, asthma, bladder and erectile dysfunction, reproduction, auditory and ocular function, pain, hemostasis (platelet aggregation, neutropenia and leukemia), neurodegeneration, and immune system function are reviewed. An alternative, complementary approach to the discovery of novel drugs interacting with the P2 receptor system is that of targeting the enzymes modulating ATP (and UTP) metabolism.…”
This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.
-The concept of a purinergic signalling system, using purine nucleotides and nucleosides as extracellular messengers, was first proposed over 30 years ago. After a brief historical review and update of purinoceptor subtypes, this article focuses on the diverse physiological roles of adenosine triphosphate, adenosine diphosphate, uridine triphosphate and adenosine. These molecules mediate short-term (acute) signalling functions in neurotransmission, secretion and vasodilation, and long-term (chronic) signalling functions in development, regeneration, proliferation and cell death. Plasticity of purinoceptor expression in pathological conditions is frequently obser ved, including an increase in the purinergic component of parasympathetic nervous control of the human bladder in interstitial cystitis and outflow obstruction, and in sympathetic cotransmitter control of blood vessels in hypertensive rats. The antithrombotic action of clopidogrel (Plavix), a P2Y 12 receptor antagonist, has been shown to be particularly promising in the prevention of recurrent strokes and heart attacks in recent clinical trials (CAPRIE and CURE). The role of P2X 3 receptors in nociception and a new hypothesis concerning purinergic mechanosensory transduction in visceral pain will be considered, as will the therapeutic potential of purinergic agonists or antagonists for the treatment of supraventricular tachycardia, cancer, dry eye, bladder hyperactivity, erectile dysfunction, osteoporosis, diabetes, gut motility and vascular disorders. KEY WORDS: purinoceptors, interstitial cystitis, thrombosis, visceral pain, cancer, osteoporosis, peripheral vascular disease, cystic fibrosis, Parkinson' s disease, kidney failure Purinergic signalling: history and receptor subtypes A seminal paper by Drury and Szent-Györgi in 1929 described the potent actions of purine nucleotides and nucleosides, adenosine triphosphate (ATP) and adenosine on the heart and blood vessels 1 . A landmark paper by Pamela Holton in 1959 showed that, during antidromic stimulation of sensory nerves, ATP was released to the rabbit ear artery in sufficient amounts to produce changes in vascular tone 2 . Then, in 1970, Burnstock et al. found evidence for the role of ATP as a neurotransmitter in nonadrenergic, noncholinergic (NANC) nerves supplying the gut 3 , and, in 1972, the word 'purinergic' was coined and the purinergic-neurotransmission hypothesis was put forward 4 (Fig 1). This concept met with considerable resistance for many years because ATP had been established as an intracellular energy source involved in various metabolic cycles, and it was thought that such a ubiquitous molecule was unlikely to be involved in selective extracellular signalling. However, the concept is now widely accepted. Later, it was established that ATP is a cotransmitter with classical transmitters in both the peripheral and the central nervous systems, and that purines are powerful extracellular messengers to non-neuronal cells, including exocrine and endocrine, secretory, endothelial, b...
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