Premium
Role of channel activation in cognitive enhancement mediated by α7 nicotinic acetylcholine receptors
Author(s) -
Briggs Clark A,
Grønlien Jens Halvard,
Curzon Peter,
Timmermann Daniel B,
Ween Hilde,
ThorinHagene Kirsten,
Kerr Paige,
Anderson David J,
Malysz John,
Dyhring Tino,
Olsen Gunnar M,
Peters Dan,
Bunnelle William H,
Gopalakrishnan Murali
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00426.x
Subject(s) - agonist , desensitization (medicine) , partial agonist , pharmacology , nicotinic agonist , allosteric regulation , receptor , allosteric modulator , chemistry , nicotinic acetylcholine receptor , in vivo , acetylcholine receptor , neuroscience , biology , biochemistry , microbiology and biotechnology
Background and purpose: Several agonists of the α7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid α7 nAChR desensitization in vitro ; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved. Experimental approach: Two structurally related α7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm. Key results: NS6784 activated human and rat α7 nAChR with EC 50 s of 0.72 and 0.88 µM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at α7 nAChR (<2% in oocytes, ≤8% in GH4C1 cells), although its agonist‐like properties were revealed by adding a positive allosteric modulator of α7 nAChRs or using the slowly desensitizing α7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A‐582941. In contrast, NS6740 did not enhance performance, but blocked effects of A‐582941. Conclusions and implications: Collectively, these findings suggest that a degree of α7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to α7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of α7 nAChR antagonists with favourable CNS penetration.