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.
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.
Whiteside
Garth T
GT
Departments of Molecular Pharmacology and Neuropharmacology, Purdue Pharma Discovery Research, 6 Cedarbrook Drive, Cranbury, NJ 08512, USA. Garth.Whiteside@pharma.com
Harrison
James E
JE
Pearson
Michelle S
MS
Chen
Zhengming
Z
Fundytus
Marian E
ME
Rotshteyn
Yakov
Y
Turchin
Paul I
PI
Pomonis
James D
JD
Mark
Lilly
L
Walker
Katharine
K
Broglé
Kevin C
KC
D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; 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 / Q000494:pharmacology*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds