RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 783
OP 792
DO 10.1124/jpet.103.063313
VO 310
IS 2
A1 Kenneth J. Valenzano
A1 Wendy Miller
A1 Zhengming Chen
A1 Shen Shan
A1 Gregg Crumley
A1 Sam F. Victory
A1 Ellen Davies
A1 Jin-Cheng Huang
A1 Nezima Allie
A1 Scott J. Nolan
A1 Yakov Rotshteyn
A1 Donald J. Kyle
A1 Kevin Broglé
YR 2004
UL http://jpet.aspetjournals.org/content/310/2/783.abstract
AB Mu opioid receptors are present throughout the central and peripheral nervous systems. Peripheral inflammation causes an increase in mu receptor levels on peripheral terminals of primary afferent neurons. Recent studies indicate that activation of peripheral mu receptors produces antihyperalgesic effects in animals and humans. Here, we describe the in vitro pharmacological and in vivo pharmacokinetic properties of a novel, highly potent, and 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). In a radioligand binding assay, DiPOA inhibited [3H]-diprenorphine binding to recombinant human mu receptors with a Ki value of ∼0.8 nM. The rank order of affinity for DiPOA binding to recombinant human opioid receptors was mu > kappa ≈ ORL-1 >> delta. DiPOA showed potent agonist effects in a human mu receptor guanosine 5′-O-(3-[35S]thio)triphosphate functional assay, with an EC50 value of ∼33 nM and efficacy of ∼85% {normalized to the mu agonist, [d-Ala2,MePhe4,Gly(ol)5]enkephalin}. Low potency agonist activity was also seen at ORL-1 and kappa receptors. DiPOA bound competitively to the opioid binding site of human mu receptors as demonstrated by a parallel rightward shift in its concentration-response curve in the presence of increasing concentrations of naltrexone. High and sustained (≥5 h) plasma levels for DiPOA were achieved following intraperitoneal administration at 3 and 10 mg/kg; central nervous system penetration, however, was ≤4% of the plasma concentration, even at levels exceeding 1500 ng/ml. As such, DiPOA represents a systemically available, peripherally restricted small molecule mu opioid agonist that will aid in understanding the role played by mu opioid receptors in the periphery.