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Purpose: To determine NCX 470 (0.1%) and Lumigan® (bimatoprost ophthalmic solution, 0.01%—LUM) intraocular pressure (IOP)-lowering activity after single or repeated (5 days) dosing along with changes in aqueous humor (AH) dynamics. Methods: Ocular hypotensive activity of NCX 470 and LUM was compared with vehicle (VEH) in Beagle dogs using TonoVet®. Non-human primates (NHP) and bioengineered three-dimensional (3D) human Trabecular Meshwork/Schlemm's Canal (HTM/HSC™) constructs exposed to transforming growth factor-β2 (TGFβ2) were used to monitor NCX 470 and LUM-induced changes in AH dynamics. Results: NCX 470 (30 μL/eye) showed greater IOP reduction compared with LUM (30 μL/eye) following single AM dosing [maximum change from baseline (CFBmax) = −1.39 ± 0.52, −6.33 ± 0.73, and −3.89 ± 0.66 mmHg (mean ± standard error of the mean) for VEH, NCX 470, and LUM, respectively]. Likewise, repeated 5 days daily dosing of NCX 470 resulted in lower IOP than LUM across the duration of the study (average IOP decrease across tests was −0.45 ± 0.22, −6.06 ± 0.15, and −3.60 ± 0.22 mmHg for VEH, NCX 470, and LUM, respectively). NCX 470 increased outflow facility (Cfl) in vivo in NHP (CflVEH = 0.37 ± 0.09 μL/min/mmHg and CflNCX470 = 0.64 ± 0.17 μL/min/mmHg) as well as in vitro (CHTM/HSC) in HTM/HSC constructs (CHTM/HSC_VEH = 0.47 ± 0.02 μL/min/mm2/mmHg and CHTM/HSC_NCX470 = 0.76 ± 0.03 μL/min/mm2/mmHg). In addition, NCX 470 increased uveoscleral outflow (FuVEH = 0.62 ± 0.26 μL/min and FuNCX470 = 1.53 ± 0.39 μL/min with episcleral venous pressure of 15 mmHg) leaving unaltered aqueous flow (AHFVEH = 2.03 ± 0.22 μL/min and AHFNCX470 = 1.93 ± 0.31 μL/min) in NHP. Conclusions: NCX 470 elicits greater IOP reduction than LUM following single or repeated dosing. Data in NHP and 3D-HTM/HSC constructs suggest that changes in Cfl and Fu account for the robust IOP-lowering effect of NCX 470. [ABSTRACT FROM AUTHOR]

In patients with ocular hypertension or glaucoma, all treatments aim to lower intraocular pressure (IOP) by modulating aqueous humour (AH) production and/or uveoscleral and trabecular meshwork/Schlemm's canal AH drainage. PG analogues are considered to be the 'gold standard' treatment and are the most frequently used IOP-lowering agents. Recent data support an important role for NO in regulating IOP. Thus, novel PG analogues carrying a NO-donating moiety were recently advanced. Latanoprostene bunod (LBN) and NCX 470, NO-donating derivatives of latanoprost and bimatoprost, respectively, are examples of such compounds. LBN ophthalmic solution, 0.024% (Vyzulta™), showed greater IOP-lowering efficacy compared with that of Xalatan® (latanoprost ophthalmic solution, 0.005%) or 0.5% timolol maleate in clinical settings. NCX 470 was found to be more effective than bimatoprost in animal models of ocular hypertension and glaucoma. Selective EP2 receptor agonists (i.e. taprenepag isopropyl, omidenepag isopropyl and aganepag isopropyl) and non-selective prostanoid receptor agonists (i.e. ONO-9054, sepetaprost isopropyl) that concomitantly stimulate FP and EP3 receptors have also been shown to hold promise as effective IOP-lowering agents. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc. [ABSTRACT FROM AUTHOR]

Adenosine A2A receptor antagonists provide a promising nondopaminergic approach to the treatment of Parkinson's disease (PD). Initial clinical trials of A2A antagonists targeted PD patients who had already developed treatment complications known as L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve symptoms while reducing existing LID. The goal of this study is to explore the effect of A2A antagonists and targeted A2A receptor depletion on the actual development of sensitized responses to L-DOPA in mouse models of LID in PD. Hemiparkinsonian mice (unilaterally lesioned with 6-OHDA) were treated daily for 3 weeks with a low dose of L-DOPA (2 mg/kg) preceded by a low dose of selective A2A antagonist (KW-6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione] at 0.03 or 0.3 mg/kg, or SCH58261 [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine] at 0.03 mg/kg) or vehicle intraperitoneally. In control mice, contralateral rotational responses to daily L-DOPA gradually increased over the initial week before reaching a persistent maximum. Both A2A antagonists inhibited the development of sensitized contralateral turning, with KW-6002 pretreatment reducing the sensitized rotational responses by up to threefold. The development of abnormal involuntary movements (a measure of LID) as well as rotational responses was attenuated by the postnatal depletion of forebrain A2A receptors in conditional (Cre/loxP system) knock-out mice. These pharmacological and genetic data provide evidence that striatal A2A receptors play an important role in the neuroplasticity underlying behavioral sensitization to L-DOPA, supporting consideration of early adjunctive therapy with an A2A antagonist to reduce the risk of LID in PD. [ABSTRACT FROM AUTHOR]

Adenosine A2A receptors (A2ARs) are well positioned to influence the maladaptive CNS responses to repeated dopaminergic stimulation in psychostimulant addiction. Expression of A2ARs in brain is largely restricted to the nucleus accumbens and striatum, where molecular adaptations mediate chronic effects of psychostimulants such as behavioral sensitization. Using a novel forebrain-specific conditional (Cre/IoxP system) knockout of the A2AR in coordination with classical pharmacological approaches, we investigated the involvement of brain A2ARs in amphetamine-induced behavioral sensitization. Tissue-specific, functional disruption of the receptor was confirmed by autoradiography, PCR, and the loss of A2A antagonist-induced motor stimulation. Daily treatment with amphetamine for I week markedly enhanced locomotor responses on day 8 in control mice and the sensitization remained robust after a week of washout. Their conditional knockout Iittermates however showed no sensitization to amphetamine on day 8 and only a modest sensitization following the washout. Pharmacolosical blockade of adenosine A2ARs also was able to block the development (but not the expression) of sensitization in multiple mouse strains. Thus activation of brain A2ARs plays a critical role in developing augmented psychomotor responses to repeated psychostimulant exposure. [ABSTRACT FROM AUTHOR]

Abstract: In the pursuit of improved treatments for Parkinson''s disease (PD), the adenosine A2A receptor has emerged as an attractive nondopaminergic target. Based on the compelling behavioral pharmacology and selective basal ganglia expression of this G-protein-coupled receptor, its antagonists are now crossing the threshold of clinical development as adjunctive symptomatic treatment for relatively advanced PD. The antiparkinsonian potential of A2A antagonism has been boosted further by recent preclinical evidence that A2A antagonists might favorably alter the course as well as the symptoms of the disease. Convergent epidemiological and laboratory data have suggested that A2A blockade may confer neuroprotection against the underlying dopaminergic neuron degeneration. In addition, rodent and nonhuman primate studies have raised the possibility that A2A receptor activation contributes to the pathophysiology of dyskinesias—problematic motor complications of standard PD therapy—and that A2A antagonism might help prevent them. Realistically, despite being targeted to basal ganglia pathophysiology, A2A antagonists may be expected to have other beneficial and adverse effects elsewhere in the central nervous system (e.g., on mood and sleep) and in the periphery (e.g., on immune and inflammatory processes). The thoughtful design of new clinical trials of A2A antagonists should take into consideration these counterbalancing hopes and concerns and may do well to shift toward a broader set of disease-modifying as well as symptomatic indications in early PD. [Copyright &y& Elsevier]

Repeated treatment with the psychostimulant amphetamine produces behavioral sensitization that may represent the neural adaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A2A receptors in psychostimulant-induced locomotor sensitization using an A2A receptor knockout (A2A KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A2A KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D1 agonist SKF81297 (2.5 mg/kg) or the D2 agonist quinpirole (1.0 mg/kg) produced similar behavioral sensitization in both WT and A2A KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A2A KO and WT mice, suggesting normal D1 and D2 receptor responsiveness. Finally, at the cellular level A2A receptor inactivation abolished the increase in striatal dynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioral sensitization in A2A KO mice suggests a critical role of the A2A receptor in the development of psychostimulant-induced behavioral sensitization, and supports the pharmacological potential of A2A adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure. [ABSTRACT FROM AUTHOR]

The effects of selective A1 and A2A adenosine receptor compounds in two mouse models of acute nociception were studied: acetic acid-induced writhing and the hot plate assays. Stimulation of A1 receptors by 2-chloro-N6-cyclopentyl-adenosine (CCPA, 0.01–0.1 mg/kg, i.p.; A1Ki=6 nM) or blockade of A2A receptors by 5-amino-7-(β-phenylethyl)-2-(8-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261, 1–10 mg/kg, i.p.; A2AKi=1.3 nM) produced anti-nociceptive effects. At the highest dose tested, CCPA and SCH58261 reduced the number of writhings by 79 and 99%, respectively. On the contrary, the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (A1Ki=2.8 nM) and the A2A agonist 2-(4-[2-carboxyethyl])phenethylamino-5′-N-ethylcarboxamido-adenosine-hydrochloride (GGS21680) produced pro-nociceptive effects in both tests. These findings suggest for the first time that blockade of A2A adenosine receptors produces anti-nociceptive effects. [Copyright &y& Elsevier]

NCX1404 [(3S)-5-methyl-3-(((1-(4-(nitrooxy)butanoyloxy)ethoxy)carbonylamino) methyl)hexanoic acid] is a novel nitric oxide (NO)-donating pregabalin that is readily absorbed and processed in vivo to pregabalin and NO. We determined the antiallodynic response of NCX1404 after acute or after 7, 14, and 21 days of repeated daily oral dosing in mice with streptozotocin (STZ)-induced painful diabetic neuropathy (PDN). Pregabalin and its combination with the NO donor isosorbide mononitrate (ISMN) were used for comparison. The blood levels of pregabalin and nitrites, used as surrogate marker of NO release, after NCX1404 or pregabalin dosing were monitored in parallel experiments using liquid chromatography with tandem mass spectrometry (LC-MS/MS). NCX1404 and pregabalin resulted in similar pregabalin levels as it was their antiallodynic activity after acute dosing in STZ mice. However, NCX1404 resulted in disease-modifying properties when administered daily for 21 days, as indicated by the time- and dose-dependent reversal of STZ-induced mechanical allodynia (paw withdrawal threshold [PWT]Veh&#95;21d= 1.3 ± 0.15 g for vehicle; PWTNCX1404&#95;21d= 1.4 ± 0.5 g, 2.9 ± 0.2 g* and 4.1 ± 0.2 g*, respectively for 19, 63, and 190μmol/kg, oral gavage [PO] of NCX1404; *P< 0.05 versus vehicle). This effect was not shared by pregabalin at equimolar doses (190μmol/kg, PO, PWTPregab&#95;21d= 1.4 ± 0.1 g*, *P< 0.05 versus equimolar NCX1404). In addition, the NO donor ISMN (52.3μmol/kg, PO) alone or combined with pregabalin (63μmol/kg) was active at 7 days (PWTVeh&#95;7d= 1.7 ± 0.16 g; PWTISMN&#95;7d= 3.9 ± 0.34 g*; PWTPregab&#95;7d= 1.3 ± 0.07 g; PWTISMN+pregab&#95;7d= 3.8 ± 0.29 g*; *P< 0.05) but not at later time points. The long-term effect of NCX1404 was independent of residual drug exposure and lasted for several days after the treatment was stopped. In summary, like pregabalin, NCX1404 is an effective antiallodynic agent. Differently from pregabalin, repeated dosing of NCX1404 re-established normal nociceptive responses in STZ-induced PDN in mice., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Adenosine A2A receptor antagonists provide a promising nondopaminergic approach to the treatment of Parkinson's disease (PD). Initial clinical trials of A2A antagonists targeted PD patients who had already developed treatment complications known as L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve symptoms while reducing existing LID. The goal of this study is to explore the effect of A2A antagonists and targeted A2A receptor depletion on the actual development of sensitized responses to L-DOPA in mouse models of LID in PD. Hemiparkinsonian mice (unilaterally lesioned with 6-OHDA) were treated daily for 3 weeks with a low dose of L-DOPA (2 mg/kg) preceded by a low dose of selective A2A antagonist (KW-6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione] at 0.03 or 0.3 mg/kg, or SCH58261 [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine] at 0.03 mg/kg) or vehicle intraperitoneally. In control mice, contralateral rotational responses to daily L-DOPA gradually increased over the initial week before reaching a persistent maximum. Both A2A antagonists inhibited the development of sensitized contralateral turning, with KW-6002 pretreatment reducing the sensitized rotational responses by up to threefold. The development of abnormal involuntary movements (a measure of LID) as well as rotational responses was attenuated by the postnatal depletion of forebrain A2A receptors in conditional (Cre/loxP system) knock-out mice. These pharmacological and genetic data provide evidence that striatal A2A receptors play an important role in the neuroplasticity underlying behavioral sensitization to L-DOPA, supporting consideration of early adjunctive therapy with an A2A antagonist to reduce the risk of LID in PD.

Adenosine A(2A) receptors (A(2A)Rs) are well positioned to influence the maladaptive CNS responses to repeated dopaminergic stimulation in psychostimulant addiction. Expression of A(2A)Rs in brain is largely restricted to the nucleus accumbens and striatum, where molecular adaptations mediate chronic effects of psychostimulants such as behavioral sensitization. Using a novel forebrain-specific conditional (Cre/loxP system) knockout of the A(2A)R in coordination with classical pharmacological approaches, we investigated the involvement of brain A(2A)Rs in amphetamine-induced behavioral sensitization. Tissue-specific, functional disruption of the receptor was confirmed by autoradiography, PCR, and the loss of A(2A) antagonist-induced motor stimulation. Daily treatment with amphetamine for 1 week markedly enhanced locomotor responses on day 8 in control mice and the sensitization remained robust after a week of washout. Their conditional knockout littermates however showed no sensitization to amphetamine on day 8 and only a modest sensitization following the washout. Pharmacological blockade of adenosine A(2A)Rs also was able to block the development (but not the expression) of sensitization in multiple mouse strains. Thus activation of brain A(2A)Rs plays a critical role in developing augmented psychomotor responses to repeated psychostimulant exposure.

The psychomotor stimulant effects of caffeine, the most widely consumed psychoactive substance, are mediated through its antagonism of extracellular adenosine receptors in the basal ganglia. In the absence of caffeine, adenosine stimulates inhibitory striatopallidal neurons that suppress motor activity by binding to A2A receptors, thereby activating a cyclic adenosine 3',5'-monophosphate (cAMP) and protein kinase A signaling pathway. Bastia and Schwarzschild discuss recent research implicating DARRP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kilodaltons) as an attractive mediator of the sustained psychomotor stimulant effect seen with low doses of caffeine. They highlight the role of postsynaptic A2A receptor blockade, but leave open the possibility that antagonism of presynaptic or postsynaptic A1 receptors also contributes to DARPP-32-dependent psychomotor stimulation by caffeine.