DiPOA ([8-(3,3-Diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic Acid), a Novel, Systemically Available, and Peripherally Restricted Mu Opioid Agonist with Antihyperalgesic Activity: II. In Vivo Pharmacological Characterization in the Rat

Abstract

Mu opioid receptors are expressed throughout the central and peripheral nervous systems. Peripheral inflammation leads to an increase in mu receptor present on the peripheral terminals of primary sensory neurons. Activation of peripheral mu receptors produces potent antihyperalgesic effects in both humans and animals. Here, we describe the in vivo pharmacological properties of the structurally novel, highly potent, systemically available yet peripherally restricted mu opioid agonist, [8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl]-acetic acid (DiPOA). DiPOA administered i.p. produced naltrexone-sensitive, dose-dependent reversal of Freund's complete adjuvant-induced inflammatory mechanical hyperalgesia (1-10 mg/kg). Maximum percent reversal (67%) was seen 1 h postadministration at 10 mg/kg (the highest dose studied). DiPOA also proved antihyperalgesic in a model of postsurgical pain with a maximum percent reversal of 85% 1 h postadministration at 30 mg/kg i.p. (the highest dose studied). DiPOA administered i.p. had no effect in the tail flick assay of acute pain (0.1-10 mg/kg), produced no ataxia as measured by latency to fall from an accelerating rotarod (3-30 mg/kg), and was not antihyperalgesic in the Seltzer model of neuropathic pain (1-10 mg/kg). This is the first report of a peripherally restricted, small-molecule mu opioid agonist that is nonsedating, antihyperalgesic, and effective against inflammatory and postsurgical pain when administered systemically.To date, four members of the opioid receptor family have been cloned and characterized, and include the mu, kappa, delta, and opioid receptor-like 1 (ORL-1) receptors (Pleuvry, 2003). All are G-protein-coupled receptors and mediate inhibition of adenylate cyclase through activation of GTP-binding proteins. In addition, opioid receptor agonism results in the opening of receptor-operated potassium channels and suppression of voltage-gated calcium currents (Duggan and North, 1983). Several classes of endogenous peptidic ligands have been identified for the opioid receptors, including the enkephalins, dynorphins, endorphins, and nociceptin (Terenius, 2000). These ligands are distributed throughout the central and peripheral nervous system (CNS and PNS) as well as in peripheral tissues.Opioid receptors are also expressed throughout the CNS, and their activation results in potent analgesia via inhibition of ascending excitatory nociceptive transmissions and activation of descending inhibitory systems (Fields and Basbaum, 1999;Yaksh, 1999). Activation of CNS opioid receptors also results in diminished responsiveness of the brainstem respiratory centers to carbon dioxide (Gutstein and Akil, 2001) and stimulation of dopaminergic pathways, particularly the Article, publication date, and citation information can be found at

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…How do alterations in opioid receptor expression (see section II.A.5.c) relate to peripheral opioid antinociception in neuropathic pain? The PSL-induced down-regulation of -receptors in the DRG (Rashid et al, 2004) was associated with a lack of effect of -agonists injected into the ipsilateral paw and of the peripherally restricted agonist DiPOA applied systemically (Aley and Levine, 2002;Rashid et al, 2004;Whiteside et al, 2004). However, insufficient dosing or injection volume may have accounted for the absence of antinociception in these studies (Aley and Levine, 2002;Rashid et al, 2004;Whiteside et al, 2004).…”

“…The PSL-induced down-regulation of -receptors in the DRG (Rashid et al, 2004) was associated with a lack of effect of -agonists injected into the ipsilateral paw and of the peripherally restricted agonist DiPOA applied systemically (Aley and Levine, 2002;Rashid et al, 2004;Whiteside et al, 2004). However, insufficient dosing or injection volume may have accounted for the absence of antinociception in these studies (Aley and Levine, 2002;Rashid et al, 2004;Whiteside et al, 2004). Suppression of opioid receptor expression by a silencer factor has also been suggested in PSL (Uchida et al, 2010).…”

DiPOA ([8-(3,3-Diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic Acid), a Novel, Systemically Available, and Peripherally Restricted Mu Opioid Agonist with Antihyperalgesic Activity: I. In Vitro Pharmacological Characterization and Pharmacokinetic Properties

“…This property is important to further understand the role of peripheral mu receptors in animal models that mimic pathophysiological conditions. To this end, Whiteside et al (2004) show that DiPOA has robust antihyperalgesic properties in rat models of inflammatory pain.…”

“…route was routinely used for all in vivo studies because the plasma DiPOA concentrations attained were significantly higher than those obtained using an oral route of administration (data not shown). In addition, this dosing range demonstrated significant antihyperalgesic effects as detailed in the accompanying manuscript (Whiteside et al, 2004). An additional group of rats dosed i.v.…”

Regioselective Synthesis of Spiro-2-aminopyrimidinone Derivatives in Ionic Liquid as Green Solvent

“…In addition, many spiro-compounds possess very promising biological activities as anticancer agents 22 , antibacterial agents 23 , anticonvulsant agents 24 , anti-tuberculosis agents 25 , anti-Alzheimer's agents 26 , pain-relief agents 27 , anti-dermatitis agents 28 and antimicrobial agents 29 . In addition to their medical uses, some spiro-compounds have found other uses in the agricultural and industrial fields.…”