2 research outputs found
New Alpha9 nAChR Ligands Based on a 5‑(Quinuclidin-3-ylmethyl)-1,2,4-oxadiazole Scaffold
No full textSeveral lines of evidence have indicated
that nicotinic
acetylcholine
receptors (nAChR) that contain α9 subunits, probably in combination
with α10 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 α7 nAChR.
Both α7- and α9-containing neuronal nAChR can be pharmacologically
distinguished from the high-affinity nicotinic receptors of the brain
by their sensitivity to α-bungarotoxin, but in other ways, they
have quite distinct pharmacological profiles. The early association
of α7 with CAS led to the development of numerous new ligands,
variously characterized as α7 agonists, partial agonists, or
silent agonists that desensitized α7 receptors without activation.
Subsequent reinvestigation of one such family of α7 ligands
based on an N,N-diethyl-N′-phenylpiperazine scaffold led to the identification
of potent agonists and antagonists for α9. In this paper, we
characterize the α9/α10 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 α9, 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 α9 antagonist,
permitting an in silico model of α9 antagonism
to be developed. The α9 activity of these compounds was confirmed
to be potentially useful for CAS management of inflammatory pain in
cell-based assays of cytokine release
