New Alpha9 nAChR Ligands Based on a 5-(Quinuclidin-3-ylmethyl)-1,2,4-oxadiazole Scaffold

Several lines of evidence have indicated that nicotinic acetylcholine receptors (nAChR) that contain alpha 9 subunits, probably in combination with alpha 10 subunits, may be valuable targets for the management of pain associated with inflammatory diseases through a cholinergic anti-inflammatory system (CAS), which has also been associated with alpha 7 nAChR. Both alpha 7- and alpha 9-containing neuronal nAChR can be pharmacologically distinguished from the high-affinity nicotinic receptors of the brain by their sensitivity to alpha-bungarotoxin, but in other ways, they have quite distinct pharmacological profiles. The early association of alpha 7 with CAS led to the development of numerous new ligands, variously characterized as alpha 7 agonists, partial agonists, or silent agonists that desensitized alpha 7 receptors without activation. Subsequent reinvestigation of one such family of alpha 7 ligands based on an N,N-diethyl-N '-phenylpiperazine scaffold led to the identification of potent agonists and antagonists for alpha 9. In this paper, we characterize the alpha 9/alpha 10 activity of a series of compounds based on a 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole (QMO) scaffold and identify two new potent ligands of alpha 9, QMO-28, an agonist, and QMO-17, an antagonist. We separated the stereoisomers of these compounds to identify the most potent agonist and discovered that only the 3R isomer of QMO-17 was an alpha 9 antagonist, permitting an in silico model of alpha 9 antagonism to be developed. The alpha 9 activity of these compounds was confirmed to be potentially useful for CAS management of inflammatory pain in cell-based assays of cytokine release.