Delving into the Latest Updates on ACEA-2085 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

ACEA-2085

Target

AMPA receptor x GlyR

Mechanism

AMPA receptor antagonists(Glutamate receptor ionotropic AMPA antagonists), GlyR antagonists(Glycine receptor antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Pain

Originator Organization

Purdue Neuroscience Co.

Active Organization-

Inactive Organization

Purdue Neuroscience Co.

Drug Highest PhaseDiscontinuedDiscovery

First Approval Date-

Regulation-

The NMDA (N-methyl-D-aspartate) receptor antagonists and the NMDA glycine site antagonists given alone have minimal effects on acute nociception. In contrast, the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor antagonists have a major role in acute nociception. We investigated the interactions among these three antagonists in acute nociception.

METHODS:

Sprague-Dawley rats (250-300 g) were implanted with chronic lumbar intrathecal catheters and were tested for their thermal withdrawal response using the hot plate test after intrathecal administration of AP-5 (NMDA receptor antagonist), ACEA 1021 (NMDA glycine site antagonist), or ACEA 2085 (AMPA receptor antagonist). The combinations of these three agents were also tested.

RESULTS:

Intrathecal administration of ACEA 2085 had a dose dependent analgesic effect while intrathecal AP-5 or ACEA 1021 could not induce dose dependent effect. Co-administration of AP-5 10 microg and ACEA 2085 intrathecally showed no changes in the thermal response latency compared with ACEA 2085 alone. ACEA 1021, 12 microg, and AP-5 showed left-ward shift of the dose effect curve only with small doses of AP-5 (1 microg, 3 microg). Only the smallest dose of ACEA 2085 (0.1 ng) with ACEA 1021 12 microg induced antinociception compared with that of ACEA 2085 alone.

CONCLUSIONS:

The combination of the NMDA glycine site antagonist and low doses of the NMDA receptor antagonist or the AMPA receptor antagonist increased the analgesic effect on acute thermal nociception with increased side effects, while the NMDA receptor antagonist and the AMPA receptor antagonist had no such interaction.

01 Sep 1998·AnesthesiologyQ1 · MEDICINE

Effects of Intrathecal NMDA and Non-NMDA Antagonists on Acute Thermal Nociception and Their Interaction with Morphine

Q1 · MEDICINE

Article

Author: Weber, Eckard ; Nishiyama, Tomoki ; Yaksh, Tony L.

Background:

N-methyl-D-aspartate (NDMA) antagonists have minimal effects on acute nociception but block facilitated states of processing. In contrast, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists decrease acute noxious responses. Morphine (a mu-opioid agonist) can also decrease acute nociceptive processing. The authors hypothesized that the interaction between morphine and AMPA receptor antagonists would be synergistic, whereas morphine and NMDA antagonists show no such interaction in acute nociception.

Methods:

Sprague-Dawley rats (weight, 250-300 g) were implanted with chronic lumbar intrathecal catheters and were assigned to receive one of several doses of morphine--ACEA 1021 (NMDA glycine site antagonist), ACEA 2085 (AMPA antagonist), AP-5 (NMDA antagonist), saline or vehicle--and were tested for their effect on the response latency using a 52.5 degrees C hot plate. The combinations of morphine and other agents also were tested.

Results:

Intrathecal morphine (ED50:2 microg/95% confidence interval, 1-4 microg) and ACEA 2085 (6 ng/2-15 ng), but not AP-5 or ACEA 1021, yielded a dose-dependent increase in the thermal escape latency. A systematic isobolographic analysis was carried out between intrathecal morphine and ACEA 2085 using the ED50 dose ratio of 357:1. A potent synergy was observed with decreased side effects. Morphine dose-response curves were carried out for morphine and fixed doses of ACEA 1021 (12 microg) or AP-5 (10 microg). No synergistic interactions were noted.

Conclusions:

Spinal mu-receptor activation and AMPA receptor antagonism showed a synergistic antinociception in response to an acute thermal stimulus. NMDA or NMDA glycine site antagonism had no effect alone nor did they display synergy with morphine. These results suggest an important direction for development of acute pain strategies may focus on the AMPA receptor.

100 Deals associated with ACEA-2085

Login to view more data