title: 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.
abstract: 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 [(3)H]-diprenorphine binding to recombinant human mu receptors with a K(i) value of approximately 0.8 nM. The rank order of affinity for DiPOA binding to recombinant human opioid receptors was mu > kappa approximately ORL-1 >> delta. DiPOA showed potent agonist effects in a human mu receptor guanosine 5'-O-(3-[(35)S]thio)triphosphate functional assay, with an EC(50) value of approximately 33 nM and efficacy of approximately 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 (> or =5 h) plasma levels for DiPOA were achieved following intraperitoneal administration at 3 and 10 mg/kg; central nervous system penetration, however, was < or =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.
authors.affiliation: Department of Molecular Pharmacology, Purdue Pharma Discovery Research, 6 Cedarbrook Drive, Cranbury, NJ 08512, USA. ken.valenzano@pharma.com
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Valenzano
authors.forename: Wendy
authors.initials: W
authors.lastname: Miller
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Chen
authors.forename: Shen
authors.initials: S
authors.lastname: Shan
authors.forename: Gregg
authors.initials: G
authors.lastname: Crumley
authors.forename: Sam F
authors.initials: SF
authors.lastname: Victory
authors.forename: Ellen
authors.initials: E
authors.lastname: Davies
authors.forename: Jin-Cheng
authors.initials: JC
authors.lastname: Huang
authors.forename: Nezima
authors.initials: N
authors.lastname: Allie
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Nolan
authors.forename: Yakov
authors.initials: Y
authors.lastname: Rotshteyn
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Kyle
authors.forename: Kevin
authors.initials: K
authors.lastname: Broglé
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001372:Aza Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013141:Spiro Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C498149:(8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro(4.5)dec-3-yl)-acetic acid; D000085:Acetates; D000701:Analgesics, Opioid; D001372:Aza Compounds; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds