Topic
CR665
About: CR665 is a research topic. Over the lifetime, 4 publications have been published within this topic receiving 127 citations. The topic is also known as: FE 200665.
Papers
TL;DR: This review focuses on the first on describing the peripheral opioidergic system and the second on the review of the current state of development of peripherally active opioid receptor agonists with their potential clinical applications.
Abstract: Background: It is established that opioid receptors are present in the dorsal root ganglia and the central as well as peripheral terminals of primary afferent neurons. Now, it has been shown that peripheral terminals of afferent nerves can be the sites of the intrinsic modulation of nociception and that opioid analgesia can be mediated by peripheral opioid receptors as well. Aim: This review focuses on two areas: the first on describing the peripheral opioidergic system, and the second on the review of the current state of development of peripherally active opioid receptor agonists with their potential clinical applications. Methods: Online and manual search using key words such as peripheral opioid receptors, peripheral (or peripherally restricted) opioid agonists, and peripheral mu-, kappa-, and delta-opioid receptor agonists, followed by full-text access and further cross-referencing. Results: The obvious theoretical advantage of using these molecules is that analgesia is achieved while avoiding the bothersome-to-dangerous centrally mediated adverse effects of centrally acting opioids. Molecules known for their central action (eg, morphine) have been used in peripheral tissues (joints, bone, teeth) with reasonable but varied success. Over the last 10-15 years, several molecules with peripherally restricted opioid agonist activity have been developed and several more are in the “clinical pipeline.” Although none is available as an approved medication till date, a few (eg, the peripherally restricted kappa-agonist FE200665, also known as CR665) have completed phase I clinical trials and currently in phase II. Others such as loperamide, which is approved for use as an antidiarrheal drug, have been found to be variably useful as a peripherally acting opioid analgesic. Conclusions: Substantive research is currently underway and this is an exciting research area for both basic and applied clinical fields. Various ways to enhance peripheral opioid analgesia are suggested.
98 citations
TL;DR: This study generated a series of derivatives of CR665 and screened them for oral activity in the acetic acid-induced rat writhing assay for peripheral pain and proposed that compound 9 is a candidate for development as an orally-available peripherally-restricted kappa agonist.
Abstract: Kappa-opioid agonists are particularly efficacious in the treatment of peripheral pain but suffer from central nervous system (CNS)-mediated effects that limit their development. One promising kappa-agonist is the peptidic compound CR665. Although not orally available, CR665 given i.v. exhibits high peripheral to CNS selectivity and benefits patients with visceral and neuropathic pain. In this study we have generated a series of derivatives of CR665 and screened them for oral activity in the acetic acid-induced rat writhing assay for peripheral pain. Five compounds were further screened for specificity of activation of kappa receptors as well as agonism and antagonism at mu and delta receptors, which can lead to off-target effects. All active derivatives engaged the kappa receptor with EC50s in the low nM range while agonist selectivity for kappa over mu or delta was >11,000-200,000-fold. No antagonist activity was detected. One compound was chosen for further analysis (Compound 9). An oral dose response of 9 in rats yielded an EC50 of 4.7 mg/kg, approaching a druggable level for an oral analgesic. To assess the peripheral selectivity of this compound an i.v. dose response in rats was assessed in the writhing assay and hotplate assay (an assay of CNS-mediated pain). The EC50 in the writhing assay was 0.032 mg/kg while no activity was detectable in the hotplate assay at doses as high as 30 mg/kg, indicating a peripheral selectivity of >900-fold. We propose that compound 9 is a candidate for development as an orally-available peripherally-restricted kappa agonist.
30 citations
TL;DR: Results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.
Abstract: Peripherally acting opioids, particularly peripheral κ-opioid agonists, may be effective for treating visceral pain by activating receptors expressed on afferent nerves within the gut. The objective of this study was to investigate the pharmacokinetic/pharmacodynamic profile of a novel peripherally selective κ-opioid agonist, CR665 (JNJ-38488502), and compare it to that of oxycodone, a non-selective brain-penetrant opioid. In a randomized, placebo-controlled, double-blind, three-way crossover study, healthy male volunteers were administered CR665 (0.36 mg/kg, intravenous), oxycodone (15 mg, oral) or placebo (intravenous and oral), followed by assessment of visceral pain tolerance thresholds (VPTT) measured as volume of water (mL) in the bag placed on an oesophageal probe. Plasma drug concentration data were used to generate pharmacokinetic models, which were then used to fit the VPTT data using NONMEM® VI to generate population pharmacokinetic/pharmacodynamic models. CR665 kinetics were optimally fitted with a two-compartment model, while oxycodone kinetics were best described by a one-compartment model with transit compartment absorption feeding directly into the central compartment. For both drugs, the plasma concentration effects on VPTT were best fit by a direct linear model, i.e. without the concentration–analgesia delay characteristic of brain-penetrant opioids. The slope of oxycodone (0.089 mL per ng/mL) was steeper than that of CR665 (0.0035 mL per ng/mL) for the plasma drug concentration acting on the VPTT. The results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.
16 citations
TL;DR: This data indicates that peripheral κ-opioid agonists may be effective for treating visceral pain by activating receptors expressed on afferent nerves within the gut.
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2013 | 2 |
| 2011 | 2 |