The α7
nicotinic acetylcholine receptor (nAChR) is a promising
drug target for a number of
neurological disorders including
chronic pain and inflammatory diseases. Since α7 can function as a
ligand-gated ion channel,
drug development initially focused on
ligands that were selective activators of the α7
ion channel. However, the best α7 drugs for
chronic pain and
inflammation indications may not be
ion channel activators but rather "silent agonists", which bind to the receptor but preferentially induce non-conducting states that modulate signal transduction in non-neuronal cells. One such compound is
NS6740. We show that
NS6740 selectively induces prolonged desensitization of α7 nAChRs. There are two forms of α7 desensitization that can be distinguished by their sensitivity to the positive allosteric modulators (PAMs). At high concentrations,
NS6740 preferentially induces PAM-insensitive desensitization, which over the course of several minutes reverts to the sensitive form.
NS6740 was tested in several
pain models after in vivo administration in the mouse. Although it had no effects in acute thermal
pain,
NS6740 induced significant dose- and time-dependent antinociceptive activity in
formalin- and
acetic acid-induced nociceptive behaviors as well as in the chronic constrictive nerve injury (CCI) model for
neuropathic pain. The antinociceptive activity of
NS6740 in these models was α7-dependent. In addition,
NS6740 administration reversed
pain-induced aversion, an important affective component of
pain. The time and concentration dependence of the effects were consistent with
NS6740 induction of PAM-insensitive non-conducting states, suggesting that signal transduction required for
analgesia is accomplished by α7 receptors in that conformation.