[Abstract Title]. - Society for Neuroscience

Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 270.12/HH11
Topic: D.08.r. Opioids and other analgesics
Title: In vivo characterization of novel, peripherally-acting opioid antagonists
Authors: *M. S. TODTENKOPF, R. L. DEAN, K. A. RICHIE, K. REITANO, D. ARNELLE,
D. R. DEAVER;
Life Sci., Alkermes, Cambridge, MA
Abstract: Opioid-induced constipation (OIC; an effect of chronic opioid use) is a severe side
effect that hinders pain management. A potential strategy is to treat with a peripherally acting
opioid antagonist without affecting analgesia. To that end, a series of non-selective, peripherallyacting
opioid antagonists were synthesized and preliminary in vivo characteristics were
examined. These compounds were initially identified as having similar properties as
methylnaltrexone, but may have greater efficacy and/or bioavailability in rodent models of gut
motility. Here we report data for four of these compounds (RDC-4253, RDC-0092, RDC-1036
and RDC-2166) in comparison to methylnaltrexone (MNTX), via intraperitoneal (IP) and oral
(PO) administration. Each compound was tested in mice in a test of gut motility. PGE2 (a
prostaglandin) induces diarrhea in mice within 15 minutes of an IP injection (0.1 mg/kg).
Pretreatment with morphine (1.0 mg/kg, IP) blocks this effect. We administered our compounds
15 minutes prior to morphine to test their ability to block morphine‟s effects. In addition, we
examined the duration of action of the minimum effective oral dose for each compound by
increasing the time between test compound and morphine administration. When given IP, each
test compound blocked morphine‟s effect comparable to MNTX. When given orally (30 mg/kg),
RDC-4253 and RDC-0092 were comparable or more effective at blocking morphine‟s effects
than MNTX, while RDC-1036 blocked morphine‟s effects at a considerably lower dose (10
mg/kg). Furthermore, when given orally (10 mg/kg), RDC-1036 had a greater effect, quicker
onset and longer duration of action (up to 8 hours) than MNTX. Finally, the ability of these
novel antagonists to block morphine-induced antinociception was assessed (PO) in the hot plate
and tail flick tests. For MNTX, 30 mg/kg (the same effective dose in the PGE2 model) reduced
morphine-induced antinociception in the hot plate test whereas doses up to 30 mg/kg did not
affect morphine-induced antinociception in the tail flick test. For RDC-4253, RDC-0092 and
RDC-2166, 30 mg/kg did not reduce morphine-induced antinociception in the hot plate or tail
flick test. For RDC-1036, 30 mg/kg slightly reduced morphine-induced antinociception in the hot
plate test but 10 mg/kg (the minimal effective dose in the PGE2 model) did not. In addition, the
effective doses in the PGE2 model did not affect morphine‟s analgesic effect in the tail flick test.
In summary, these novel opiate antagonists are peripherally-acting, orally active, more potent
and longer acting than MNTX, and may be potential therapeutics for OIC with minimal effects
on morphine analgesia.
Disclosures: M.S. Todtenkopf , Alkermes, Inc., A. Employment (full or part-time); R.L. Dean,
Alkermes, Inc., A. Employment (full or part-time); K.A. Richie, Alkermes.com, A. Employment
(full or part-time); K. Reitano, Alkermes, Inc., A. Employment (full or part-time); D. Arnelle,