Title:Allosteric Modulation of Nicotinic Acetylcholine Receptors: The Concept and Therapeutic Trends
Volume: 22
Issue: 14
Author(s): Victor V. Uteshev
Affiliation:
Keywords:
Allosteric, cognitive, nociceptive, inflammatory, protection, ischemic, stroke, traumatic, choline, nicotinic, PNU-120596,
PNU120596.
Abstract: Expressing functional nicotinic acetylcholine receptors (nAChRs) may be beneficial to central neurons
and neuronal networks because activation of nAChRs enhances neuronal resistance to injury, improves attention,
cognitive performance, and produces robust anti-inflammatory and analgesic effects in mammals. Although exogenous
orthosteric nAChR ligands present valuable tools in treatment of age- and trauma-related neurological deficits,
therapeutic approaches that could amplify the brain’s innate ability to maintain cholinergic homeostasis and
resist injury may serve as intriguing and promising alternatives and have not been fully explored. One of these
novel approaches utilizes positive allosteric modulators (PAMs) of nAChRs. Because of the ubiquitous expression
of nAChRs in neuronal, glial and immune tissues, highly selective PAMs could amplify multiple endogenous neuroprotective,
pro-cognitive, anti-inflammatory and anti-nociceptive cholinergic pathways to offset cholinergic hypofunction
and generate therapeutic efficacy by targeting only a single player: i.e., nAChRs activated by endogenous cholinergic tone. In
this article, I review the concept of allosteric modulation and current trends in therapeutic applications of nicotinic PAMs.
