N6-Cyclopentyladenosine

Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine and kappa-opioid receptors in rat spinal cord nociceptive reflexes.[Pubmed:25325292]

Behav Pharmacol. 2014 Dec;25(8):741-9.

Antinociception induced by the adenosine A1 receptor agonist N6-Cyclopentyladenosine (CPA) is linked to opioid receptors. We studied the subtype of receptors to which CPA action is related, as well as a possible enhancement of antinociception when CPA is coadministered with opioid receptor agonists. Spinal cord neuronal nociceptive responses of male Wistar rats with inflammation were recorded using the single motor unit technique. CPA antinociception was challenged with naloxone or norbinaltorphimine. The antinociceptive activity of fentanyl and U-50488H was studied alone and combined with CPA. Reversal of CPA antinociception was observed with norbinaltorphimine (82.9+/-13% of control) but not with low doses of naloxone (27+/-8% of control), indicating an involvement of kappa-opioid but not micro-opioid receptors. Low doses of CPA did not modify fentanyl antinociception. However, a significant enhancement of the duration of antinociception was seen when U-50488H was coadministered with CPA. We conclude that antinociception mediated by CPA in the spinal cord is associated with activation of kappa-opioid but not micro-opioid receptors in inflammation. In addition, coadministration of CPA and kappa-opioid receptor agonists is followed by significantly longer antinociception, opening new perspectives in the treatment of chronic inflammatory pain.

Highly selective A(1) -adenosine-agonist (2-chloro-N6-cyclopentyladenosine) and reduction of flap necrosis in adipocutaneous flaps in rats.[Pubmed:22038887]

Head Neck. 2012 Aug;34(8):1100-5.

BACKGROUND: The 2-chloro-N6-Cyclopentyladenosine (CCPA) was proven to be a protective factor in ischemic reperfusion injury in myocardium and to reduce the infarct size in the heart. The purpose of this study was to determine whether flap necrosis could be reduced by intravenous administration of CCPA. METHODS: Fifty-six male Wistar rats were divided into 4 experimental groups. An epigastric adipocutaneous flap was raised, and the area of flap necrosis was assessed for all groups on the fifth postoperative day with planimetry software. RESULTS: The control group had a significantly lower rate of flap necrosis than the ischemic control group (p < .05). The nonischemic CCPA group had a significantly lower rate of flap necrosis than the nonischemic control group (p < .05). The ischemic CCPA group had a highly significant (p < .0001) rate of lower flap necrosis than the ischemic control group. CONCLUSION: Our data show that reduction of flap necrosis can be achieved both with and without ischemic periods by intravenous administration of CCPA.

An adenosine A1 agonist 2-chloro-N6 cyclopentyladenosine inhibits the angiotensin II-induced cardiomyocyte hypertrophy through the calcineurin pathway.[Pubmed:25277512]

Cardiology. 2014;129(3):153-62.

OBJECTIVES: The aim of this investigation was to study the underlying mechanism of an adenosine A1 receptor agonist 2-chloro-N6 cyclopentyladenosine (CCPA) inhibiting cardiomyocyte hypertrophy induced by angiotensin II (AngII). METHODS: Neonatal rat cardiomyocytes were treated with AngII to generate a cardiomyocyte hypertrophy model. Cardiomyocyte cultures were randomized into 5 groups: control; AngII; AngII + cyclosporin A (CsA); AngII + CCPA, and AngII + CCPA + DPCPX. Cardiomyocyte viability was measured by MTT assay. Protein synthesis was assessed by the application of (3)H leucine ((3)H-Leu) incorporation into protein. The mRNA expressions of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (beta-MHC) and calcineurin Abeta (CnAbeta) were measured by real-time quantitative PCR. The protein level of CnAbeta was dissected by Western blotting. RESULTS: AngII administration at lower concentrations increased the cardiomyocytes viabilities gradually. Surface area, mRNA expressions of ANP, BNP and beta-MHC, and (3)H-Leu incorporation of AngII-induced cardiomyocytes were increased in a dose-dependent manner. As a calcineurin-specific inhibitor, CsA inhibited (3)H-Leu incorporation, surface area, mRNA expressions of ANP, BNP, beta-MHC, CnAbeta and protein expression of CnAbeta of AngII-induced cardiomyocytes. CCPA also suppressed the mRNA and protein expressions of CnAbeta and exerted antihypertrophic effects to a greater degree than CsA. The inhibition of CCPA on cardiomyocyte hypertrophy was counteracted by the A1 receptor antagonist DPCPX. CONCLUSION: The A1 receptor agonist CCPA could significantly inhibit AngII-induced cardiomyocyte hypertrophy via the calcineurin signaling pathway.

Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and opioid receptors in spinal cord nociceptive reflexes.[Pubmed:23810661]

Life Sci. 2013 Aug 14;93(5-6):233-9.

AIMS: We previously observed that the adenosine A1 receptor agonist N6-Cyclopentyladenosine (CPA) is a very effective antinociceptive agent on intact but not on spinalized adult rats with inflammation. Since a close connection between opioid and adenosine A1 receptors has been described, we studied a possible relationship between these systems in the spinal cord. MAIN METHODS: CPA-mediated antinociception was challenged by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT) and by the opioid receptor antagonist naloxone on male adult Wistar rats with carrageenan-induced inflammation. Withdrawal reflexes activated by noxious mechanical and electrical stimulation were recorded using the single motor technique in intact and sham-spinalized animals. KEY FINDINGS: CPA was very effective in intact and sham spinalized rats but not in spinalized animals. Full reversal of CPA antinociception was observed with i.v. 1mg/kg of naloxone but not with 20mg/kg of CPT i.v. in responses to noxious mechanical and electrical stimulation. CPT fully prevented CPA from any antinociceptive action whereas naloxone did not modify CPA activity. These results suggest a centrally-mediated action, since CPA depressed the wind-up phenomenon which is derived of the activity of spinal cord neurons. SIGNIFICANCE: The present study provides strong in vivo evidence of an antinociceptive activity mediated by the adenosine A1 receptor system in the spinal cord, linked to an activation of opioid receptors in adult animals with inflammation.

Adenosine receptors and their ligands.[Pubmed:11111832]

Naunyn Schmiedebergs Arch Pharmacol. 2000 Nov;362(4-5):382-91.

The regulatory actions of adenosine are mediated via four subtypes of G protein-coupled receptors distinguished as A1, A2A, A2B and A3 receptors. Their presence on basically every cell makes them an interesting target for the pharmacological intervention in many pathophysiological situations. A large number of ligands have been synthesized over the last two decades and provide agonists and antagonists that are more or less selective for the known receptor subtypes. In addition, many radioligands are available in tritiated or radioiodinated form. The comparative pharmacological characterization of all four human adenosine receptor subtypes revealed that some of the compounds thought to be selective from data in other species have unexpected potencies at human receptors. As a result, compounds that exhibit high affinity to only one subtype are an exception. Although the selection of ligands is immense, it is less than satisfying for most subtypes of adenosine receptors.

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the effects of N6-cyclopentyladenosine analogs on heart rate in rat: estimation of in vivo operational affinity and efficacy at adenosine A1 receptors.[Pubmed:9353402]

J Pharmacol Exp Ther. 1997 Nov;283(2):809-16.

We have developed a pharmacokinetic-pharmacodynamic strategy based on the operational model of agonism to obtain estimates of apparent affinity and efficacy of N6-Cyclopentyladenosine (CPA) analogs for the adenosine A1 receptor-mediated in vivo effect on heart rate in the rat. All analogs investigated produced a significant decrease of the heart rate after intravenous infusion. Individual concentration-effect curves were fitted to the operational model of agonism with the values of Emax and n constrained to the intrinsic activity (273 bpm) and Hill slope (1.18), respectively, obtained with the agonist that displayed the highest intrinsic activity, 5'-deoxy-CPA. In all cases, the model converged and estimates of apparent affinity and efficacy were obtained for each agonist. Affinity estimates correlated well with pKi values for the adenosine A1 receptor in rat brain homogenates. In addition, a highly significant correlation was found between the estimates of the in vivo efficacy parameter and the GTP shift (the ratio between Ki in the presence and absence of GTP). In conclusion, the operational model of agonism can provide meaningful measures of agonist affinity and efficacy at adenosine A1 receptors in vivo. The model should be of use in the development of partial adenosine A1 receptor agonists.

Behavioral and cardiovascular effects of analogs of adenosine in cynomolgus monkeys.[Pubmed:3572798]

J Pharmacol Exp Ther. 1987 Apr;241(1):76-83.

The behavioral and cardiovascular effects of six metabolically stable analogs of adenosine were studied in cynomolgus monkeys. Behavioral effects were determined in monkeys trained to respond under a 30-response fixed-ratio (FR) schedule of food presentation; cardiovascular effects were evaluated in a separate group of unanaesthetized monkeys seated at rest. Dose-effect curves for each drug were determined by administering cumulative doses i.v. during sequential components of the experimental session. All six analogs of adenosine produced dose-related decreases in FR responding with the following order of potency: 5'N-ethylcarboxamide adenosine (NECA) greater than 2-chloroadenosine (2-CA) greater than N6-R-phenylisopropyladenosine (R-PIA) greater than N6-Cyclopentyladenosine (CPA) greater than N6-cyclohexyladenosine (CHA) greater than N6-S-phenylisopropyladenosine (S-PIA). In cardiovascular studies, all drugs except CPA produced dose-related decreases in mean blood pressure (MBP) with the following order of potency: NECA greater than 2-CA = R-PIA greater than CHA greater than S-PIA. CPA did not alter MBP at doses that decreased both FR responding and heart rate (HR). All drugs except NECA produced dose-related decreases in HR with the following order of potency: CPA greater than 2-CA greater than R-PIA greater than CHA greater than S-PIA. NECA increased HR at doses that decreased MPB and FR responding. Doses of caffeine that did not alter FR responding or cardiovascular function when given alone antagonized the behavioral effects of R-PIA, CHA, CPA and NECA. Caffeine also antagonized the effects of R-PIA, CHA and NECA on MBP and the effects of R-PIA and CPA on HR.(ABSTRACT TRUNCATED AT 250 WORDS)

N6-Cyclopentyladenosine (CPA) is a selective Adenosine A1 receptor agonist, with Ki values of 2.3 nM, 790 nM and 43 nM for human A1, A2A and A3 receptors, respectively.

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