Purine and Pyrimidine (P2) Receptors as Drug Targets

Jacobson, Kenneth A.; Jarvis, Michael F.; Williams, Michael

doi:10.1021/jm020046y

Cited by 325 publications

(326 citation statements)

References 410 publications

(924 reference statements)

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“…The available drugs do not allow complete elucidation of the role of each receptor due to their actions on several P2 receptor subtypes. For example, BzATP is considered the most specific agonist for the P2X7 receptors, but it has more potent actions on other P2X receptors [85].…”

Section: Future Directionsmentioning

confidence: 99%

“…In addition, the available receptor antagonists are weak, may have different sensitivities depending on the species [85], or may have other pharmacological actions, like suramin, which can antagonize G-proteins [86]. In many cases, there are no specific antibodies that would enable us to establish the expression pattern of each receptor.…”

Section: Future Directionsmentioning

confidence: 99%

“…It is possible that ATP degradation products are responsible for some of the effects of ATP on synaptic plasticity and neuroprotection [88]. Studies on the pharmacological profile of P2 receptors may also be affected by the action of ectonucleotidases, as rapid degradation of the agonists can diminish their potency and result in a pharmacological profile that depends on agonist stability rather than the true binding affinity for the receptor [85]. In addition, the expression pattern of ectonucleotidases overlaps in vivo and it has not been easy to assign specific roles of these enzymes to each purinergic pathway [89].…”

Section: Future Directionsmentioning

confidence: 99%

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Physiological and pathological functions of P2X7 receptor in the spinal cord

Cotrina

Nedergaard

2009

Purinergic Signalling

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ATP-mediated signaling has widespread actions in the nervous system from neurotransmission to regulation of proliferation. In addition, ATP is released during injury and associated to immune and inflammatory responses. Still, the potential of therapeutic intervention of purinergic signaling during pathological states is only now beginning to be explored because of the large number of purinergic receptors subtypes involved, the complex and often overlapping pharmacology and because ATP has effects on every major cell type present in the CNS. In this review, we will focus on a subclass of purinergic-ligand-gated ion channels, the P2X7 receptor, its pattern of expression and its function in the spinal cord where it is abundantly expressed. We will discuss the mechanisms for P2X7R actions and the potential that manipulating the P2X7R signaling pathway may have for therapeutic intervention in pathological events, specifically in the spinal cord.

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Section: Future Directionsmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

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Physiological and pathological functions of P2X7 receptor in the spinal cord

Cotrina

Nedergaard

2009

Purinergic Signalling

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“…ATP triggers neuronal excitation through several different subtypes of P2 purinoceptors. ATP is a nonselective agonist with varied potencies for each of the seven ionotropic P2X and eight metabotropic P2Y purinoceptor subtypes currently identified (Ralevic & Burnstock, 1998;Bianchi et al, 1999;Jacobson et al, 2002;Abbracchio et al, 2003). Receptor localization and behavioral studies suggest that more than one of these receptor subtypes is involved in the transmission of peripheral and/or spinal nociceptive signals (Collo et al, 1996;Vulchanova et al, 1996;Cockayne et al, 2000;Souslova et al, 2000;Okada et al, 2002;Yoshida et al, 2002;Tsuda et al, 2003;Wismer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Existing P2 receptor agonists nonselectively activate a variety of P2 receptor subtypes, and are metabolically labile (Jacobson et al, 2002). We have recently reported that systemic administration of A-317491 (Figure 1), the first non-nucleotide antagonist that has high affinity and selectivity for blocking P2X 3 homomeric and P2X 2/3 heteromeric channels, is antinociceptive in rat models of chronic inflammatory and neuropathic pain .…”

Section: Introductionmentioning

confidence: 99%

Effects of A‐317491, a novel and selective P2X₃/P2X_2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration

McGaraughty

Wismer

Zhu

et al. 2003

British J Pharmacology

170

129

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1 We have recently reported that systemic delivery of A-317491, the first non-nucleotide antagonist that has high affinity and selectivity for blocking P2X 3 homomeric and P2X 2/3 heteromeric channels, is antinociceptive in rat models of chronic inflammatory and neuropathic pain. In an effort to further evaluate the role of P2X 3 /P2X 2/3 receptors in nociceptive transmission, A-317491 was administered either intrathecally or into the hindpaw of a rat in several models of acute and chronic nociception. 2 Intraplantar (ED 50 ¼ 300 nmol) and intrathecal (ED 50 ¼ 30 nmol) injections of A-317491 produced dose-related antinociception in the CFA model of chronic thermal hyperalgesia. Administration of A-317491 by either route was much less effective to reduce thermal hyperalgesia in the carrageenan model of acute inflammatory hyperalgesia. 3 Intrathecal, but not intraplantar, delivery of A-317491 attenuated mechanical allodynia in both the chronic constriction injury and L5-L6 nerve ligation models of neuropathy (ED 50 ¼ 10 nmol for both models). Intrathecal injections of A-317491 did not impede locomotor performance. 4 Both routes of injection were effective in reducing the number of nocifensive events triggered by the injection of formalin into a hindpaw. Nocifensive behaviors were significantly reduced in both the first and second phases of the formalin assay (intrathecal ED 50 ¼ 10 nmol, intraplantar ED 50 4300 nmol). Nocifensive behaviors induced by the P2X receptor agonist a,b-meATP were also significantly reduced by intraplantar injection of A-317491. 5 These data indicate that both spinal and peripheral P2X 3 /P2X 2/3 receptors have significant contributions to nociception in several animal models of nerve or tissue injury. Intrathecal administration of A-317491 appears to be more effective than intraplantar administration to reduce tactile allodynia following peripheral nerve injury.

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High Throughput Functional Assays for P2X Receptors

2012

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Adenosine triphosphate (ATP) activates two receptor superfamilies, metabotropic P2Y and ionotropic P2X receptors. The P2X receptors are nonselective cation channels that are widely expressed on excitable cells including neurons, glia, and smooth muscle cells. The protocols in this unit are useful for evaluating ligands that interact with P2X receptors on native cells or that are cloned and expressed in recombinant heterologous cell systems. Calcium imaging methods are described for the pharmacological characterization of fast or slowly desensitizing P2X receptors. While these methods are readily applicable to a wide variety of ligand-gated ion channels, the protocols provided herein detail how they can be used to measure activation of homomeric P2X3 (fast desensitizing) and heteromeric P2X2/3 (slowly desensitizing) receptors. Appropriate agonists and/or calcium dyes can be substituted to assess activity at other P2X receptor subtypes. An additional protocol is provided for measuring P2X7 receptor-mediated pore formation in THP-1, a native human acute monocytic leukemia cell line that can be used to study homomeric P2X7 (non-desensitizing) receptors that are expressed on macrophages and microglial cells.

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Purine and Pyrimidine (P2) Receptors as Drug Targets

Cited by 325 publications

References 410 publications

Physiological and pathological functions of P2X7 receptor in the spinal cord

Physiological and pathological functions of P2X7 receptor in the spinal cord

Effects of A‐317491, a novel and selective P2X₃/P2X_2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration

High Throughput Functional Assays for P2X Receptors

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Purine and Pyrimidine (P2) Receptors as Drug Targets

Cited by 325 publications

References 410 publications

Physiological and pathological functions of P2X7 receptor in the spinal cord

Physiological and pathological functions of P2X7 receptor in the spinal cord

Effects of A‐317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration

High Throughput Functional Assays for P2X Receptors

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Effects of A‐317491, a novel and selective P2X₃/P2X_2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration