In vivo and in vitro ADMET profiling and in vivo pharmacodynamic investigations of a selective α7 nicotinic acetylcholine receptor agonist with a spirocyclic Δ2-isoxazoline molecular skeleton

Abstract

(±)-3-Methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate (±)-1 was previously characterized as the most selective agonist at α7 neuronal nicotinic acetylcholine receptors in a series of spirocyclic quinuclidinyl-Δ²-isoxazoline derivatives. In this study, we performed different in vitro biological assays aimed at characterizing the ADMET properties of (±)-1. Then, we tested the compound in vivo in behavioral studies including classical novel object recognition and inhibitory avoidance tests in the rat, and a spatial memory assay in zebrafish involving a rapid T-maze task. The results indicated an overall favorable profile for (±)-1 in view of potential therapeutic applications targeting the central nervous system.

Keywords: Agonist; Episodic memory passive avoidance test; Learning/memory in zebrafish; Novel object recognition test; eADMET; α7 Nicotinic acetylcholine receptors.