The therapeutic promise of positive allosteric modulation of nicotinic receptors

Eur J Pharmacol. 2014 Mar 15:727:181-5. doi: 10.1016/j.ejphar.2014.01.072. Epub 2014 Feb 12.


In the central nervous system, deficits in cholinergic neurotransmission correlate with decreased attention and cognitive impairment, while stimulation of neuronal nicotinic acetylcholine receptors improves attention, cognitive performance and neuronal resistance to injury as well as produces robust analgesic and anti-inflammatory effects. The rational basis for the therapeutic use of orthosteric agonists and positive allosteric modulators (PAMs) of nicotinic receptors arises from the finding that functional nicotinic receptors are ubiquitously expressed in neuronal and non-neuronal tissues including brain regions highly vulnerable to traumatic and ischemic types of injury (e.g., cortex and hippocampus). Moreover, functional nicotinic receptors do not vanish in age-, disease- and trauma-related neuropathologies, but their expression and/or activation levels decline in a subunit- and brain region-specific manner. Therefore, augmenting the endogenous cholinergic tone by nicotinic agents is possible and may offset neurological impairments associated with cholinergic hypofunction. Importantly, because neuronal damage elevates extracellular levels of choline (a selective agonist of α7 nicotinic acetylcholine receptors) near the site of injury, α7-PAM-based treatments may augment pathology-activated α7-dependent auto-therapies where and when they are most needed (i.e., in the penumbra, post-injury). Thus, nicotinic-PAM-based treatments are expected to augment the endogenous cholinergic tone in a spatially and temporally restricted manner creating the potential for differential efficacy and improved safety as compared to exogenous orthosteric nicotinic agonists that activate nicotinic receptors indiscriminately. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs.

Keywords: (R)-5-(2-azetidinylmethoxy)-2-chloropyridine; 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; 3-(2,4-dimethoxybenzylidene)-anabaseine); Analgesia; Cerebral ischemia; Choline; Nicotinic acetylcholine receptor; PNU-120596; Positive allosteric modulator; choline chloride (PubChem CID: 6209); epibatidine (PubChem CID: 854023); i.e., ABT-594 (PubChem CID: 3075702); i.e., DMXB-A (PubChem CID: 6438361); i.e., PNU-120596 (PubChem CID: 311434).

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Analgesics / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / therapeutic use
  • Central Nervous System / drug effects*
  • Central Nervous System / metabolism
  • Central Nervous System / physiopathology
  • Drug Design
  • Humans
  • Molecular Targeted Therapy
  • Neuroprotective Agents / therapeutic use
  • Nicotinic Agonists / therapeutic use*
  • Nootropic Agents / therapeutic use
  • Receptors, Nicotinic / drug effects*
  • Receptors, Nicotinic / metabolism
  • Signal Transduction / drug effects


  • Analgesics
  • Anti-Inflammatory Agents
  • Neuroprotective Agents
  • Nicotinic Agonists
  • Nootropic Agents
  • Receptors, Nicotinic