Affiliations: Department of Pharmaceutical Sciences, College of
Pharmacy, Midwestern University, Glendale, AZ, USA | Instituto de Investigaciones Bioquímicas de
Bahía Blanca, Universidad Nacional del Sur, CONICET, Bahía Blanca, Argentina
Note: [] Correspondence: Hugo R. Arias, Department of Pharmaceutical
Sciences, College of Pharmacy, Midwestern University, 19555 N. 59th Ave.,
Glendale, AZ 85308, USA. Tel.: +1 623 572 3589; Fax: +1 623 572 3550; E-mail: harias@midwestern.edu
Abstract: Nicotinic acetylcholine receptors (AChRs) are the best characterized
ion channels representing the Cys-loop receptor superfamily. AChRs have all the
machinery to recognize the neurotransmitter ACh and other agonists such as
nicotine, and to transduce the agonist-induced conformational changes into the
opening of the intrinsic cation channel. The gating machinery couples ligand
binding, located at the extracellular portion, to the opening of the ion
channel, located at the transmembrane region. The interface between the
extracellular and the transmembrane domains is considered one of the most
important structural and functional features for the process of gating. And
finally, in the prolonged presence of agonists, the AChR becomes desensitized.
Several drugs affect the functioning of these receptors. Among them, positive
allosteric modulators (PAM) have acquired importance since are novel drugs for
several neurological diseases. PAMs do not bind to the orthostetic binding
sites but allosterically enhance the activity elicited by agonists by
increasing the gating process and/or by decreasing desensitization. Instead,
negative allosteric modulators (NAMs) produce the opposite effects.
Interestingly, this negative effect is similar to that found for another class
of allosteric drugs, i.e. non competitive antagonists (NCAs). However, the main
difference between both categories of drugs is based on their distinct binding
site locations. Although both NAMs and NCAs do not bind to the agonist sites,
NACs bind to sites located in the ion channel, whereas NAMs bind to nonluminal
sites. Interestingly, PAMs and NAMs might be developed as potential medications
for the treatment of several diseases involving AChRs including, dementia-,
skin-, and immunological-related diseases, drug addiction, and cancer. More
exciting is the potential combination of specific agonists with PAMs. However,
we are still in the beginning of understanding how these compounds act and how
these drugs can be used therapeutically.
