The Antinociceptive Activity of (E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor

Abstract

BACKGROUND: The primary objective of this study was to characterize the pharmacological and behavioral activity of 2 novel compounds, DM497 [(E)-3-(thiophen-2-yl)-N-(p-tolyl)acrylamide] and DM490 [(E)-3-(furan-2-yl)-N-methyl-N-(p-tolyl)acrylamide], structural derivatives of PAM-2, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR). METHODS: A mouse model of oxaliplatin-induced neuropathic pain (2.4 mg/kg, 10 injections) was used to test the pain-relieving properties of DM497 and DM490. To assess possible mechanisms of action, the activity of these compounds was determined at heterologously expressed α7 and α9α10 nAChRs, and voltage-gated N-type calcium channel (CaV2.2) using electrophysiological techniques. RESULTS: Cold plate tests indicated that 10 mg/kg DM497 was able to decrease neuropathic pain in mice induced by the chemotherapeutic agent oxaliplatin. In contrast, DM490 induced neither pro- nor antinociceptive activity but inhibited DM497’s effect at equivalent dose (30 mg/kg). These effects are not a product of changes in motor coordination or locomotor activity. At α7 nAChRs, DM497 potentiated whereas DM490 inhibited its activity. In addition, DM490 antagonized the α9α10 nAChR with >8-fold higher potency than that for DM497. In contrast, DM497 and DM490 had minimal inhibitory activity at the CaV2.2 channel. Considering that DM497 did not increase the mouse exploratory activity, an indirect anxiolytic mechanism was not responsible for the observed antineuropathic effect. CONCLUSIONS: The antinociceptive activity of DM497 and the concomitant inhibitory effect of DM490 are mediated by opposing modulatory mechanisms on the α7 nAChR, whereas the involvement of other possible nociception targets such as the α9α10 nAChR and CaV2.2 channel can be ruled out.